(R)-chiral halogenated substituted N-phenoxy N-phenyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity

ABSTRACT

The invention relates to substituted aryl and heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanol compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Novel high yield, stereoselective processes for the preparation of the chiral substituted alkanol compounds from chiral and achiral intermediates are described. Preferred (R)-Chiral 1-Subsbitutedamino-(n+1)-Alkanol compounds are substituted (R)-Chiral N-phenoxy N-phenyl aminoalcohols. A preferred specific (R)-Chiral N-phenoxy N-phenyl aminoalcohol is the compound:

This is a divisional of pending U.S. patent application Ser. No. 09/401,915, filed Sep. 23, 1999.

FIELD OF THE INVENTION

This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions, methods for treating atherosclerosis and other coronary artery disease, and methods for making compounds of this invention. More particularly, the invention relates to (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanol compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.

BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.

Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDU/LDL ratios. Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDU/LDL ratios, and to check the progress and/or formation of these diseases.

CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993); Sitori, Pharmac. Ther., 67,443-47 (1995)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795, 743-480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994)) and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18, E894-E902 (1988))) describe proteins from human plasma that inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. (J. Peptide Res., 51, 216-225 (1998)) disclose a decapeptide inhibitor of CETP. A depsipeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80 (1998).

There have been several reports of non-peptidic compounds that act as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5,605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No. 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6, 919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4-H-1,2,4-triazole-thiol as a CETP inhibitor. Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662.

Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents. One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1-amines. These are reported to be β3-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, Fisher et al. disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and artherosclerotic diseases. In European Patent Application No. 818448, Schmidt et al. describe tetrahydroquinoline derivatives as cholesteryl ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer protein inhibitors. In WO Patent Application No. 09839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describes N-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic group. U.S. Pat. No. 2,700,686 further describes a process to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reacting halogenated-1,2-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.

SUMMARY OF THE INVENTION

The present invention provides chiral compounds that can be used to inhibit cholesteryl ester transfer protein (CETP) activity and that have the general structure:

In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the chiral compounds of this invention and a pharmaceutically acceptable carrier.

In another aspect, this invention relates to methods of using these chiral inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile. The compounds and methods of this invention can also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaernia (chylomicronernia and hyperapobetalipoproteinemia), peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of this invention would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals such as primates, rabbits, pigs, horses, and the like.

DESCRIPTION OF THE INVENTION

The present invention relates to a class of compounds comprising (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I-H (also referred to herein as generic polycyclic aryl and heteroaryl (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols):

or a pharmaceutically-acceptable salt thereof, wherein;

n is an integer selected from 1 through 4;

X is oxy;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₁₆ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R₄, R₈, R₉, R₁₃, R₁₄, and R₁₅ to form a heterocyclyl ring having from 5 through 10 contiguous members;

D₁, D₂, J₁, J₂ and K₁ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂, J₁, J₂and K₁ can be N;

D₃, D₄, J₃, J₄ and K₂ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, no more than two of D₃, D₄, J₃, J₄ and K₂ can be O and S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

R₂ is hydrido;

R₂ can be selected from the group consisting of hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, perhaloaryl, perhaloaralkyl, perhaloaralkyl, heteroaralkyltthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dicyanoalkyl, carboalkoxycyanoalkyl, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q;

R₃ is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, acylamido, alkoxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is selected from a group consisting of a covalent single bond, (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2 and (CH(R₁₄))_(g)—W—(CH(R₁₄))_(p) wherein g and p are integers independently selected from 0 through 1;

R₁₄ is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy , amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R₉ and R₁₃ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R₄ and R₈ to form a heterocyclyl having from 5 through 8 contiguous members with the proviso that, when Y is a covalent bond, an R₁₄ substituent is not attached to Y;

R₁₄ and R₁₅ can be taken together to form a spacer selected from a moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₁₄ and R₁₄, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;

R₁₄ and R₁₄, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

W is selected from the group consisting of O, C(O), C(S), C(O)N(R₁₄, C(S)N(R₁₄, (R₁₄NC(O), (R₁₄NC(S), S, S(O), S(O)₂, S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is selected from other than halo and cyano;

Z is independently selected from a group consisting of a covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 1 with the proviso that, when Z is a covalent single bond, an R₁₅ substituent is not attached to Z;

R₁₅ is independently selected, when Z is (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R₄ and R₈ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R₉ and R₁₃ to form a heterocyclyl having from 5 through 8 contiguous members;

R₁₅ and R₁₅, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;

R₅ and R₁₅, when bonded to the same atom, can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;

R₁₅ is independently selected, when Z is (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 1, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a linear moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R₄ and R₈ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a linear moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R₉ and R₁₃ to form a heterocyclyl ring having from 5 through 8 contiguous members;

R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the proviso that there are one to five non-hydrido ring substituents R₄, R₅, R₆, R₇, and R₈ present, that there are one to five non-hydrido ring substituents R₉, R₁₀, R₁₁, R₁₂, and R₁₃ present, and R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time;

R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R₄ and R₉, R₄ and R₁₃, R₈ and R₉, and R₈ and R₁₃ can be used at the same time;

R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a C8 to C13 heterocyclyl ring having from 8 through 13 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R₅ and R₁₀, R₅ and R₁₂, R₇ and R₁₀, and R₇ and R₁₂ can be used at the same time.

In a another embodiment of compounds of Formula I-H,

D₁, D₂, J₁, J₂ and K₁ are each carbon with the proviso that at least one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consisting of O, S, and N, wherein D₃, D₄, J₃, J₄ and K₂ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can be N;

D₁, D₂, J₁, J₂ and K₁ can be selected from the group consisting of C, O, S, N and covalent bond with the provisos that D₃, D₄, J₃, J₄ and K₂ are each carbon and at least one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consisting of O, S, and N wherein, when D₁, D₂, J₁, J₂ and K₁ are selected from the group consisting of C, O, S, covalent bond, and N, no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂, J₁, J₂ and K₁ be N;

n is an integer selected from 1 through 4;

X is oxy;

R₁₆ is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(A)Q wherein A is Formula (II) and Q is Formula (III);

R₂ is hydrido;

R₂ can be selected from the group consisting of aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl with the provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 1;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈ can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can he used at the same time.

In an even more specific embodiment of compounds Formula I-H,

D₁, D₂, J₁, J₂ and K₁ are each carbon;

D₃, D₄, J₃, J₄ and K₂ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D₃, D₄, J₃, J₄ and K₂ is selected from the group consisting of O, S, and N, wherein no more than one of D₃, D₄, J₃, J₄ and K₂ can be a covalent bond, no more than one of D₃, D₄, J₃, J₄ and K₂ can be O, no more than one of D₃, D₄, J₃, J₄ and K₂ can be S, one of D₃, D₄, J₃, J₄ and K₂ must be a covalent bond when two of D₃, D₄, J₃, J₄ and K₂ are O and S, and no more than four of D₃, D₄, J₃, J₄ and K₂ can the N;

n is an integer selected from 1 to 3;

X is oxy;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, henzoyl, dimethyl tert -butylsilyl, hydrido, and trimethylsilyl;

R₂ is hydrido;

R₂ can be selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, 2,2,3,3,3-pentafluoropropyl, and pentafluorophenoxymethyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl with the provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In another even more specific embodiment of compounds Formula I-H,

D₃, D₄, J₃, J₄ and K₂ are each carbon;

D₁, D₂, J₁, J₂ and K₁ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D₁, D₂, J₁, J₂ and K₁ is selected from the group consisting of O, S, and N, wherein no more than one of D₁, D₂, J₁, J₂ and K₁ can be a covalent bond, no more than one of D₁, D₂, J₁, J₂ and K₁ can be O, no more than one of D₁, D₂, J₁, J₂ and K₁ can be S, one of D₁, D₂, J₁, J₂ and K₁ must be a covalent bond when two of D₁, D₂, J₁, J₂ and K₁ are O and S, and no more than four of D₁, D₂, J₁, J₂and K₁ can be N;

n is an integer selected from 1 to 3;

X is oxy;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyl tert -butylsilyl, hydrido, and trimethylsilyl;

R₂ is hydrido;

R₂ can be selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, 2,2,3,3,3-pentafluoropropyl, and pentafluorophenoxymethyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(A)Q;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl with the provisos that (CHR₃)_(n)—N(A)Q has a lower Cahn-Ingold-Prelog stereocherical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In a preferred embodiment of compounds of Formula I-H, the compounds correspond to the Formula I-C (also referred to herein as phenyl (R)chiral halogenated 1-substitutedamino-(n+1)-alkanols):

or a pharmacuetically acceptable salt thereof, wherein;

n is an integer selected from 1 through 4;

R₁₆ is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R₄, R₈, R₉, and R₁₃ to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bond when R₂ is alkyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is hydrido;

R₂ can be selected from the group consisting of aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 1;

W is selected from the group consisting of O, C(O), C(S), C(O)N(R₁₄), C(S)N(R₁₄), (R₁₄)NC(O), (R₁₄) NC(S), S, S(O), S(O)₂, S(O)₂N(R₁₄), (R₁₄)NS(O)₂, and N(R₁₄) with the proviso that R₁₄ is other than cyano;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a preferred embodiment of compounds of Formula I-C,

n is an integer selected from 1 through 4;

R₁₆ is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)-N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is hydrido;

R₂ can be selected from the group consisting of aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is selected from the group consisting of covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 1;

W is oxy;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

R₄ and R₅, R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R₄ and R₅, R₅ and R₆, R₆and R₇, and R₇ and R₇ and R₈ can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In a more preferred embodiment of compounds of Formula I-C,

n is an integer selected from 1 through 2;

R₁ is selected from the group consisting of haloalkyl and haloalkoxymethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₁₆ is hydrido;

R₂ is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is selected from the group consisting of a covalent single bond and alkylene;

Z is selected from the group consisting of a covalent single bond and alkylene;

R₁₄ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R₁₅ is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.

In an even more preferred embodiment of compounds of Formula I-C,

n is the integer 1;

R₁₆ is hydrido;

R₁ is haloalkyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is hydrido;

R₂ can be selected from the group consisting of alkyl, haloalkyl, aryl, and haloalkoxy with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, alkyl, and haloalkyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is alkylene;

Z is covalent single bond;

R₁₄ is hydrido;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and halo;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.

In an embodiment of compounds of Formula I-C,

n is an integer selected from 1 to 3;

R₁ is selected from the group consisting of trifluoromethyl,

1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₁₆ is selected from the group consisting of acetyl, benzoyl, dimethyl tert -butylsilyl, hydrido, and trimethylsilyl;

R₂ is hydrido;

R₂ can be selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, 2,2,3,3,3-pentafluoropropyl, and and pentafluorophenoxymethyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In a preferred embodiment of compounds of Formula I-C, compounds have the Formula I-CP:

or a phamaceutically acceptable salt thereof, wherein;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is hydrido;

R₂ can be selected from the group consisting of methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In a even more preferred embodiment of compounds of Formula I-CP,

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is hydrido;

R₂ can be selected from the group consisting of methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In a most preferred embodiment of compounds of Formula I-CP,

R₁ is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Ap)Qp wherein Ap is Formula (II-P) and Qp is Formula (III-P);

R₂ is hydrido;

R₂ can be phenyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Ap)Qp;

R₃ is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl with the provisos that (CHR₃)_(n)—N(Ap)Qp has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In another embodiment of compounds of Formulas I-H or I-C, the compounds correspond to the Cyclo I-H Formulas:

wherein:

K₁ and K₂ are independently selected from the group consisting of C and N;

n is an integer selected from 1 through 3;

R₁ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Apch)Qph wherein Apch is Formula (II-PCH) and Qph is Formula (III-PH);

R₂ is hydrido;

R₂ is selected from the group consisting of aryl, aralkyl, alkyl, alkenyl, alkoxyalkyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, dicyanoalkyl, and carboalkoxycyanoalkyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Apch)Qph;

R₃ is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl with the provisos that (CHR₃)_(n)—N(Apch)Qph has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂;

Y is selected from the group consisting of a covalent single bond and (C(R₁₄)₂)_(q) wherein q is an integer selected from 1 through 2;

R₁₄ is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

Z is selected from the group consisting of covalent single bond, (C(R₁₅)₂)_(q) wherein q is an integer selected from 1 through 2, and (CH(R₁₅))_(j)—W—(CH(R₁₅))_(k) wherein j and k are integers independently selected from 0 through 1;

W is selected from the group consisting of O, C(O), S, S(O), and S(O)₂;

R₁₅ is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;

R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;

R₅ and R₆, R₆ and R₇, R₇ and R₈, R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R₅ and R₆, R₆ and R₇, and R₇ and R₈, can be used at the same time and that no more than one of the group consisting of spacer pairs R₉ and R₁₀, R₁₀ and R₁₁, R₁₁ and R₁₂, and R₁₂ and R₁₃ can be used at the same time.

In an embodiment of compounds of Formula Cyclo I-H,

n is the integer 1;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the proviso that R₁ has a higher Cahn-Ingold-Prelog stereochemical system ranking than both R₂ and (CHR₃)_(n)—N(Apch)Qph wherein Apch is Formula (II-PCH) and Qph is Formula (III-PH);

R₂ is hydrido;

R₂ is selected from the group consisting of phenyl, 4-trifluoromethylphenyl, vinyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, and 2,2,3,3,3-pentafluoropropyl with the proviso that R₂ has a lower Cahn-Ingold-Prelog system ranking than both R₁ and (CHR₃)_(n)—N(Apch)Qph;

R₃ is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the provisos that (CHR₃)_(n)—N(Apch)Qph has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In another embodiment of compounds of Formula Cyclo I-H,

n is the integer 1;

R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;

R₂ is hydrido;

R₃ is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl with the provisos that (CHR₃)_(n)—N(Apch)Qph has a lower Cahn-Ingold-Prelog stereochemical system ranking than R₁ and a higher Cahn-Ingold-Prelog stereochemical system ranking than R₂.

In a preferred embodiment of compounds of Formulas I-H, I-C, I-CP, and Cyclo I-H,

Y is selected from the group consisting of methylene, ethylene, and ethylidene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro with the proviso that there is no R₄, R₈, R₉, or R₁₃ when the embodiment is a compound of Formula Cyclo I-H;

R₅ and R₁₀ are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazoltyl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;

R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In an even more preferred embodiment of compounds of Formulas I-H, I-C, I-CP, and Cyclo I-H,

Y is methylene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro with the proviso that there is no R₄, R₈, R₉, or R₁₃ when the embodiment is a compound of Formula Cyclo I-H;

R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy,3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluorotrifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methylmethylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl,tert -butoxy, 3-tert -butylphenoxy, 4-tert -butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;

R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.

In a most preferred embodiment of compounds of Formulas I-H, I-C, I-CP, and Cyclo I-H,

Y is methylene;

Z is covalent single bond;

R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido and fluoro with the proviso that there is no R₄, R₈, R₉, or R₁₃ when the embodiment is a compound of Formula Cyclo I-H;

R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert -butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy;

R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, isobutyl, isopropoxy, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio;

R₆ and R₁₁ are independently selected from the group consisting of fluoro and hydrido;

R₇ and R₁₂ are independently selected from the group consisting of hydrido and fluoro.

DEFINITIONS

The use of generic terms in the description of the compounds are herein defined for clarity.

Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol “C” represents a carbon atom. The symbol “O” represents an oxygen atom. The symbol “N” represents a nitrogen atom. The symbol “P,” represents a phosphorus atom. The symbol “S” represents a sulfur atom. The symbol “H” represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., Cl represents chlorine, Se represents selenium, etc.).

As utilized herein, the term “alkyl”, either alone or within other terms such as “haloalkyl” and “alkylthio”, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.

The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a “hydroxyl” radical, one hydrido radical may be attached to a carbon atom to form a “methine” radical (═CH—), or two hydrido radicals may be attached to a carbon atom to form a “methylene” (—CH₂—) radical.

The term “carbon” radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.

The term “cyano” radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.

The term “hydroxyalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.

The term “alkanoyl” embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.

The term “alkylene” radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, ethylidene, methylethylene, and isopropylidene.

The term “alkenylene” radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH₂═C), 1,2-vinylidene (—CH═CH—), and 1,4-butadienyl (—CH═CH—CH═CH—).

The term “halo” means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are “lower haloalkyl” radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term “hydroxyhaloalkyl” embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of “hydroxyhaloalkyl” radicals include hexafluorohydoxypropyl.

The term “haloalkylene radical” denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are “lower haloalkylene” radicals having one to about six carbon atoms. Examples of “haloalkylene” radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.

The term “haloalkenyl” denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term “alkoxyalkyl” also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” and “haloalkoxyalkyl” radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.

The terms “alkenyloxy” and “alkenyloxyalkyl” embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term “alkenyloxyalkyl” also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are “lower alkenyloxy” radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The “alkenyloxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkenyloxy” radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.

The term “haloalkoxyalkyl” also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term “haloalkenyloxy” also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term “haloalkenyloxyalkyl” also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term “alkylenedioxy” radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of “alkylenedioxy” radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term “haloalkylenedioxy” radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of “haloalkylenedioxy” radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term “fused” means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term “fused” is equivalent to the term “condensed”. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term “perhaloaryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.

The term “heterocyclyl” embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and I to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4-H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4 thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl” group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heterocyclic radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO₂—. “Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. “Alkylsulfonylalkyl”, embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. “Haloalkylsulfonyl”, embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. “Haloalkylsulfonylalkyl”, embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term “aminosulfonyl” denotes an amino radical attached to a sulfonyl radical.

The term “sulfinyl”, whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals —S(O)—. “Alkylsulfinyl”, embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. “Alkylsulfinylalkyl”, embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. “Haloalkylsulfinyl”, embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. “Haloalkylsulfinylalkyl”, embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.

The term “heteroaralkyl” embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term “perhaloaralkyl” embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.

The term “aralkylsulfinyl”, embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. “Aralkylsulfinylalkyl”, embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aralkylsulfonyl”, embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. “Aralkylsulfonylalkyl”, embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “cycloalkyl” embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term “cycloalkenyl” embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term “halocycloalkyl” embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are “lower halocycloalkyl” radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term “halocycloalkenyl” embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.

The term “cycloalkoxy” embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term “cycloalkoxyalkyl” also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The “cycloalkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “halocycloalkoxy” and “halocycloalkoxyalkyl” radicals.

The term “cycloalkylalkoxy” embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.

The term “cycloalkenyloxy” embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term “cycloalkenyloxyalkyl” also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The “cycloalkenyloxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “halocycloalkenyloxy” and “halocycloalkenyloxyalkyl” radicals.

The term “cycloalkylenedioxy” radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of “alkylenedioxy” radicals include 1,2-dioxycyclohexylene.

The term “cycloalkylsulfinyl”, embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above. “Cycloalkylsulfinylalkyl”, embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term “Cycloalkylsulfonyl”, embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. “Cycloalkylsulfonylalkyl”, embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “cycloalkylalkanoyl” embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.

The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having one to six carbon atoms. An, example of “lower alkylthio” is methylthio (CH₃—S—). The “alkylthio” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkylthio” radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

The term “alkyl aryl amino” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.

The terms alkylamino denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.

The terms arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.

The term “aralkylamino”, embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes “monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes “monoaralkyl monoalkylamino” containing one aralkyl radical and one alkyl radical attached to an amino radical.

The term “arylsulfinyl” embraces radicals containing an aryl radical, as defined above, attached to a divalent S(═O) atom. The term “arylsulfinylalkyl” denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.

The term “arylsulfonyl”, embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. “arylsulfonylalkyl”, embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term “heteroarylsulfinyl” embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(═O) atom. The term “heteroarylsulfinylalkyl” denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term “Heteroarylsulfonyl”, embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. “Heteroarylsulfonylalkyl”, embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term “aryloxy” embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tert -butylphenoxy, 3-pentafluoroethylphenoxy, and 3-(1,1,2,2-tetrafluoroethoxy)phenoxy.

The term “aroyl” embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.

The term “aralkanoyl” embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are “lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.

The term “aryloxyalkyl” embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.

The term “haloaryloxyalkyl” embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.

The term “heteroaroyl” embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.

The term “heteroaralkanoyl” embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.

The term “heteroaralkoxy” embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are “lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.

The term “haloheteroaryloxyalkyl” embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.

The term “heteroarylamino” embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.

The term “heteroarylaminoalkyl” embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.

The term “heteroaryloxy” embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.

The term “heteroaryloxyalkyl” embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.

The term “arylthio” embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.

The term “arylthioalkyl” embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.

The term “alkylthioalkyl” embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term “alkoxyalkyl” embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.

The term “carbonyl” denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term “carboxy” embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “carboxamide” embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term “carboxamidoalkyl” embraces carboxamide radicals, as defined above, attached to an alkyl group. The term “carboxyalkyl” embraces a carboxy radical, as defined above, attached to an alkyl group. The term “carboalkoxy” embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “carboaralkoxy” embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term “monocarboalkoxyalkyl” embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term “dicarboalkoxyalkyl” embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term “monocyanoalkyl” embraces one cyano radical, as defined above, attached to an alkyl group. The term “dicyanoalkylene” embraces two cyano radicals, as defined above, attached to an alkyl group. The term “carboalkoxycyanoalkyl” embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.

The term “acyl”, alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkyl alkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of “acyl” are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term “haloalkanoyl” embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl. The term “diacyl”, alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene, alkoxyalkylene, aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl. Examples of “diacyl” are phthaloyl, malonyl, succinyl, adipoyl, and the like.

The term “benzylidenyl” radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds. One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring. The methylene group is designated for attached to the lowest numbered position. Examples include the base compound benzylidene of structure:

The term “phenoxylidenyl” radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment point is through the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure:

The term “phosphono” embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term “dialkoxyphosphono” denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term “diaralkoxyphosphono” denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term “dialkoxyphosphonoalkyl” denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term “diaralkoxyphosphonoalkyl” denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.

Said “alkyl”, “alkenyl”, “alkynyl”, “alkanoyl”, “alkylene”, “alkenylene”, “benzylidenyl”, “phenoxylidenyl”, “hydroxyalkyl”, “haloalkyl”, “haloalkylene”, “haloalkenyl”, “alkoxy”, “alkenyloxy”, “alkenyloxyalkyl”, “alkoxyalkyl”, “aryl”, “perhaloaryl”, “haloalkoxy”, “haloalkoxyalkyl”, “haloalkenyloxy”, “haloalkenyloxyalkyl”, “alkylenedioxy”, “haloalkylenedioxy”, “heterocyclyl”, “heteroaryl”, “hydroxyhaloalkyl”, “alkylsulfonyl”, “haloalkylsulfonyl”, “alkylsulfonylalkyl”, “haloalkylsulfonylalkyl”, “alkylsulfinyl”, “alkylsulfinylalkyl”, “haloalkylsulfinylalkyl”, “aralkyl”, “heteroaralkyl”, “perhaloaralkyl”, “aralkylsulfonyl”, “aralkylsulfonylalkyl”, “aralkylsulfinyl”, “aralkylsulfinylalkyl”, “cycloalkyl”, “cycloalkylalkanoyl”, “cycloalkylalkyl”, “cycloalkenyl”, “halocycloalkyl”, “halocycloalkenyl”, “cycloalkylsulfinyl”, “cycloalkylsulfinylalkyl”, “cycloalkylsulfonyl”, “cycloalkylsulfonylalkyl”, “cycloalkoxy”, “cycloalkoxyalkyl”, “cycloalkylalkoxy”, “cycloalkenyloxy”, “cycloalkenyloxyalkyl”, “cycloalkylenedioxy”, “halocycloalkoxy”, “halocycloalkoxyalkyl”, “halocycloalkenyloxy”, “halocycloalkenyloxyalkyl”, “alkylthio”, “haloalkylthio”, “alkylsulfinyl”, “amino”, “oxy”, “thio”, “alkylamino”, “arylamino”, “aralkylamino”, “arylsulfinyl”, “arylsulfinylalkyl”, “arylsulfonyl”, “arylsulfonylalkyl”, “heteroarylsulfinyl”, “heteroarylsulfinylalkyl”, “heteroarylsulfonyl”, “heteroarylsulfonylalkyl”, “heteroarylamnino”, “heteroarylaminoalkyl”, “heteroaryloxy”, “heteroaryloxylalkyl”, “aryloxy”, “aroyl”, “aralkanoyl”, “aralkoxy”, “aryloxyalkyl”, “haloaryloxyalkyl”, “heteroaroyl”, “heteroaralkanoyl”, “heteroaralkoxy”, “heteroaralkoxyalkyl”, “arylthio”, “arylthioalkyl”, “alkoxyalkyl”, “acyl” and “diacyl” groups defined above may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

The term “spacer” can include a covalent bond and a linear moiety having a backbone of 1 to 7 continous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from ═C(H)—, ═C(R₁₇)—, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —N(R₁₇)—, —N═, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—, ═C(OR₁₇)—, and —C(O)— wherein R₁₇ is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, —O—, —O—CH₂—, —S—CH₂—, —CH₂CH₂—, ethenyl, —CH═CH(OH)—, —OCH₂O—, —O(CH₂)₂O—, —NHCH₂—, —OCH(R₁₇)O—, —O(CH₂CHR₁₇)O—, —OCF₂O—, —O(CF₂)₂O—, —S—, —S(O)—, —S(O)₂—, —N(H)—, —N(H)O—, —N(R₁₇)O—, —N(R₁₇)—, —C(O)—, —C(O)NH—, —C(O)NR₁₇—, —N═, —OCH₂—, —SCH₂—, S(O)CH₂—, —CH₂C(O)—, —CH(OH)—, ═C(OH)—, —CH(OR₁₇)—, ═C(OR₁₇)—, S(O)₂CH₂—, and —NR₁₇CH₂— and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

Chiral compounds of the present invention have a hydroxyl group substitutent on a chiral carbon of the alkanol and propanol compounds of the present invention specifically in the R-stereoisomeric configuration based on the Cahn-Ingold-Prelog convention for stereoisomeric carbon atoms. The R-stereoisomeric configuration compounds of the present invention may optionally have one or more additional chiral carbons present in each compound. The R-stereoisomeric configuration compounds of the present invention can exist in tautomeric, geometric, and other stereoisomeric forms. The present invention having a hydroxyl group substitutent on a chiral carbon of the alkanol and propanol compounds in the R-stereoisomeric configuration contemplates all such forms of said invented compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, diastereomers, and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The standard definitions for the Cahn-Ingold-Prelog convention and stereochemical system can be found in Pure Applied Chemistry, 1976, Vol. 45, pages 15-30 and Cahn et al., Angewandte Chemie International Edition English, 1966, Vol. 5, pages 385-415.

The terms “cis” and “trs” denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (“cis”) or on opposite sides of the double bond (“trans”).

Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or “E” and “Z” geometric forms.

Some of the compounds described contain one or more stereocenters in addition to said hydroxyl group substitutent on a chiral carbon of the alkanol and propanol compounds in the R-stereoisomeric configuration and are meant to include R, S, and mixtures of R and S forms for each additional stereocenter present.

Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the “keto” form and in part or principally as one or more “enol” forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms.

Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the “keto” form and in part or principally as one or more “enol” forms of each amide group present Compounds of the present invention having amidic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms. Said amide carbonyl groups may be both oxo (C═O) and thiono (C═S) in type.

Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the “imine” form and in part or principally as one or more “enamine” forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms.

The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: “AA” represents amino acids, “BINAP” represents 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “Boc” represents tert-butyloxycarbonyl, “BOP” represents benzotriazol-1-yl-oxy-tris-(dimethylamino), “bu” represents butyl, “dba” represents dibenzylideneacetone, “DCC” represents 1,3-dicyclohexylcarbodiimide, “DIBAH” represents diisobutylaluminum hydride, “DIPEA” represents diisopropylethylamine, “DMF” represents dimethylformamide, “DMSO” represents dimethylsulfoxide, “Fmoc” represents 9-fluorenylmethoxycarbonyl, “LDA” represents lithium diisopropylamide, “PHTH” represents a phthaloyl group, “pnZ” represents 4-nitrobenzyloxycarbonyl, “PTC” represents a phase transfer catalyst, “p-TsOH” represents paratoluenesulfonic acid, “TBAF” represents tetrabutylammonium fluoride, “TBTU” represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, “TEA” represents triethylamine, “TFA” represents trifluoroacetic acid, “THF” represents tetrahydrofuran, “TMS” represents trimethylsilyl, and “Z” represents benzyloxycarbonyl.

The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula I-H:

or a pharmaceutically-acceptable salt thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, X, Y, and Z are as defined above for the compounds of Formula I-H.

As a further embodiment, compounds of the present invention of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP or a pharmaceutically-acceptable salt thereof as defined above comprise a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP of the present invention or a pharmaceutically-acceptable salt thereof.

Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formula I-H would be also useful in prevention of cerebral vascular accident (CVA) or stroke.

Also included in the family of compounds of Formula I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP are the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-H may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula V-H include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamnine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula I-H by reacting, for example, the appropriate acid or base with the compound of Formula I-H.

Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula I-H in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.

The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient In the case of microcapsules, the encapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

The present invention further comprises a process for the preparation of (R)-chiral compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP by reacting suitable secondary amines with (R)-chiral forms of alcohols, epoxides, and cyclic sulfate esters.

The present invention also comprises a process for the preparation of (R)-chiral compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP by reacting a suitable secondary amine with a substantially stoichiometric amount of a (R)-chiral epoxide in the presence of a transition metal-based salt.

The present invention also comprises a process for the preparation of (R)-chiral precursor compounds useful in the preparation of compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP by reacting a suitable primary amine with a substantially stoichiometric amount of a (R)-chiral epoxide with or without the presence of an added transition metal-based compound.

All mentioned references are incorporated by reference as if here written.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

GENERAL SYNTHETIC PROCEDURES

The compounds of the present invention can be synthesized, for example, according to the following procedures of Schemes 1 through 58 below, wherein the substituents are as defined for Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP above except where further noted.

Synthetic Schemes 1 and 2 shows the preparation of compounds of formula XIII (“Generic Secondary Amines”) which are intermediates in the preparation of the compounds of the present invention corresponding to Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) wherein A and Q are independently aryl and heteroaryl. Schemes 1 and 2, taken together, prepare 1-substitutedamino-2-alkanols of the present invention by addition of a halogenated, oxygen containing precursor to a secondary amine to introduce an oxy containing alkyl group wherein the two groups making up the secondary amine both are made up of aromatic groups or both groups contain aromatic rings wherein said aromatic rings maybe 0 to 2 aryl rings and 0 to 2 heteroaryl rings.

The “Generic Imine” corresponding to Formula XII can be prepared through dehydration techniques generally known in the art and the preferred technique depending on the nature of “Generic Amine-1” of Formula X by reacting it with the “Generic Carbonyl Compound” of Formula XI. For example, when Z is a covalent bond, methylene, methine substituted with another subsitutent, ethylene, or another subsituent as defined in Formula I-H, the two reactants (X and XI) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the “Generic Imine” of Formula XII. Alternately, when Z is an oxygen, the “Generic Iine” is an oxime derivative. Oxime type “Generic Imine” compounds are readily prepared from the corresponding O-substituted hydroxylamine and the appropriate aldehyde or ketone type “Generic Carbonyl Compound”. Suitable procedures are described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons and by Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference. Alternately, when Z is a nitrogen, the “Generic Imine” is a hydrazone derivative. Hydrazone type “Generic Imine” compounds are readily prepared from the corresponding hydrazine and the appropriate aldehyde or ketone type “Generic Carbonyl Compound”. Suitable procedures for forming the hydrazone imines are also described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and by Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference.

Scheme 1 shows the preparation of “Generic Imine” compounds in which the amine functionality is bonded to Z; Z is bonded to A; and Y is bonded to Q. One of skill in the art will recognize that A and Q as defined can be structurally interchanged to prepare “Generic Imine” compounds with similar, identical or different structures.

The “Generic Secondary Amines” of Formula XIII can be prepared from the corresponding “Generic Imine” of Formula XII in several ways.

For example, in one synthetic scheme (Reduction Method-1), which is preferred when Z is a nitrogen, the “Generic Imine” hydrazone of Formula XII is partially or completely dissolved in lower alkanols such as ethanol or like solvent containing sufficient organic acid such as acetic acid or mineral acid such as HCl or sulfuric acid to neutralize the hydrazone as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U.S. Pat. Nos. 3,359,316 and 3,334,017, which are incorporated herein by reference. The resulting mixture is then hydrogenated at 0-100° C., more preferrably 20-50° C., and most preferrably between 20-30° C. and pressures of 10-200 psi hydrogen or more preferrably between 50-70 psi hydrogen in the presence of a noble metal catalyst such as PtO₂. The mixture is cooled, and a base such as sodium carbonate or sodium hydroxide added until the solution is neutral to just alkaline (pH 6-8).

Isolation of the desired product can be accomplished, for example, by removing the ethanol, adding water, and extracting the aqueous-organic mixture twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous magnesium sulfate, and concentrated in vacuo to yield the “Generic Secondary Amines” hydrazine of Formula XIII. If needed the “Generic Secondary Amines” hydrazine can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

In another synthetic scheme (Reduction Method-2), which is preferrred when Z is a single bond or carbon, the “Generic Imine” of Formula XII is slurried in a lower alcohol such as ethanol, methanol or like solvent at 0-10° C. and solid sodium borohydride is added in batches over 5-10 minutes at 0-10° C. with stirring. The reaction mixture is stirred below 10° C. for 30-90 minutes and then is warmed gradually to 15-30° C. After about 1-10 hours, the mixture is cooled and acid is added until the aqueous layer was just acidic (pH 5-7).

Isolation of the desired product can be accomplished, for example, by extracting the aqueous layer twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous MgSO4, and concentrated in vacuo to yield the “Generic Secondary Amines” amine, aniline, or amine of Formula XIII. If needed the “Generic Secondary Amines” amine, aniline, or amine derivative can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

In yet another synthetic scheme (Reduction Method-3), which is preferrred when Z is an oxygen, the “Generic Imine” oxime of Formula XII is slurried in a lower alcohol solvent such methanol or like solvent at 0-10° C. and acidified to a pH less than 4. Solid sodium cyanoborohydride is added in batches over 30-90 minutes at 0-20° C. with stirring and addition of a suitable organic or mineral acid to keep the pH at or below 4. The reaction mixture is stirred and warmed gradually to about 20-25° C. After about 1-10 hours, the mixture is cooled and base added until the mixture was just slightly alkaline.

Isolation of the desired product can be accomplished, for example, by removing the methanol or other low boiling solvent in vacuo. The residue is slurried with water and aqueous-organic mixture is extracted twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous MgSO₄, and concentrated in vacuo to yield the “Generic Secondary Amines” hydroxylamine of Formula XIII. If needed the “Generic Secondary Amines” hydroxylamine can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

The “Generic Secondary Amines” of Formula XIII can also be prepared, according to Scheme 1 by two alkylation procedures based on the nucleophilic substitution of bromides by amines. In one procedure, “Generic Amine-1” of Formula X is reacted with “Generic Bromide-1” of Formula XXI. In another alkylation procedure, “Generic Amine-2” of Formula XXII is reacted together with “Generic Bromide-2” of Formula XXIII.

In one synthetic alkylation scheme (Alkylation Method-1), a “Generic Amine-1” of Formula X is reacted with a “Generic Bromide-2” of Formula XXIII as described in Vogel's Textbook of Practical Organic Chemistry, Fifth Edition, 1989, pages 902 to 905 and references cited therein all of which are incorporated herein by reference. In this procedure, the “Generic Amine-1” is placed in a reaction vessel equipped with a reflux condenser with the capability to either cool or heat the vessel as dictated by the reaction. A suitable “Generic Amine-1” will be selected from primary amine and primary aromatic amine classes of compounds. Cooling may be needed and used should the reaction prove strongly exothermic. Heating may be needed and used to drive the reaction to completion. A suitable solvent may also be used to dissolve the “Generic Amine-1”. Suitable solvents are hydrocarbons such as toluene, hexane, xylene, and cyclohexane, ethers, amides such as dimethylformamide, esters such as ethyl acetate, ketones such as acetone, and nitrites such as acetonitrile or mixtures of two or more of these solvents. A suitable base is also added to the reaction vessel. Suitable bases include cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate. The base will normally be added in at least a stoichmetric quantity compared to the “Generic Amine-1” so as to neutralize liberated acid as it forms.

The “Generic Bromide-1” of Formula XXI is then added to the reaction vessel in portions so as to minimize the rate of heat evolution and minimize the concentration of the “Generic Bromide-1”. The “Generic Bromide-1” will be selected from primary and secondary organic alkyl and substituted alkyl halide compounds. The halide will preferrably be a bromide although iodides and chlorides may also be generally used. One of skill in the art will also be able to readily select and utilize organic alkyl and substituted alkyl compounds containing readily displaceable primary and secondary groups such as tosylates, mesylates, triflates, and the like. Alternately, the halides can be generally prepared from the corresponding alcohols by reaction with, for example, concentrated hydrohalic acids such as HBr or by reaction with phosphorus trihalides such as PBr₃ as described in Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference. The appropriate alcohols can be converted to tosylates, mesylates, and triflates using procedures described below.

Addition of the “Generic Bromide-1” is carried out over a period of a few minutes to several hours at temperatures between 0 and 150° C. Preferrably, the addition will take 30-120 minutes at a temperature of 0 to 50° C. The reaction can be stiffed until completion. Completion can be monitored, for example, spectroscopically using nuclear magnetic resonance or chromatographically using thin layer, liquid, or gas chromatographic procedures. If the reaction does not proceed to completion, the reactants may be heated until completion is obtained and verified.

Isolation of the desired product can be accomplished, for example, when a water immiscible solvent was used for the reaction, by adding water to the finished reaction. Additional base such as sodium carbonate can be added to ensure the reaction is basic (pH of 9 to 11). The organic layer containing the “Generic Secondary Amine” is washed with saturated brine, dried with a drying agent such as anhydrous MgSO₄, and concentrated in vacuo to yield the “Generic Secondary Amine” amine, aniline, or amine of Formula XIII. If needed the “Generic Secondary Amine” amine, aniline, or amine derivative can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.

In a second synthetic alkylation scheme (Alkylation Method-2), a “Generic Amine-2” of Formula XXII is reacted with a “Generic Bromide-2” of Formula XXIII in a method employing palladium catalyzed carbon-nitrogen bond formation. Suitable procedures for this conversion are described in Wage and Buchwald, J. Org. Chem. (1996), 61, 7240-7241, Wolfe, Wage and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters (1997), 38(36), 6359-6362 and references cited therein all of which are incorporated herein by reference. The preferred “Generic Bromide-2” of Formula XXIII are generally aryl bromides, aryl triflates, and heteroaryl bromides.

The “Generic Amine-1” and “Generic Amine-2” amines, hydroxylamines, and hydrazines, the “Generic Carbonyl Compound” aldehydes, ketones, hydrazones, and oximes, and “Generic Bromide-1” and “Generic Bromide-2” halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the “Generic Secondary Amine” compounds are available from commercial sources, can be prepared by one skilled in the art from published procedures, and/or can be obtained using specific procedures shown in Schemes 42, 43, and 44. Commercial sources include but are not limited to Aldrich Chemical, TCI-America, Lancaster-Synthesis, Oakwood Products, Acros Organics, and Maybridge Chemical. Disclosed procedures for “Generic Amine” amines, hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc., Perkin Trans.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J. Am. Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett. (1981), 22(35), 3331-4; U.S. Pat. No. 5,306,718; EP No. 314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss Patent No. CH 441366; U.S. Pat. Nos. 3,359,316 and 3,334,017; and references cited therein which are incorporated herein by reference. Representative specific “Generic Secondary Amine” of Formula XIII compounds useful for the preparation of compounds of the present invention are listed in Tables 3, 4, and 5.

TABLE 3 Structure of “Secondary Phenyl Amine” Reagents. (XIIIA)

Reagent Number R₄ R₅ R₆ R₇ R₉ R₁₀ R₁₁ Y R₁₄ 1N H phenoxy H H H OCF₂CF₂H H CH H 2N H OCF₃ H H H OCF₂CF₂H H CH H 3N F H H F H OCF₂CF₂H H CH H 4N H F H H H OCF₂CF₂H H CH H 5N H phenoxy H H H OCF₃ H CH H 6N H OCF₃ H H H OCF₃ H CH H 7N H H phenyl H H OCF₃ H CH H 8N H phenyl H H H OCF₃ H CH H 9N H H H H H OCF₃ H CH H 10N H Br H H H OCF₃ H CH H 11N H CF₃ F H H CF₃ H CH H 12N H CH₃ H H H CF₃ H CH H 13N H CF₃ H H H CF₃ H CH H 14N H CH₃ H H H OCF₃ H CH H 15N H F F H H OCF₃ H CH H 16N H Br H H H CF₃ H CH H 17N H CF₃ F H H OCF₃ H CH H 18N H F H H H OCF₃ H CH H 19N H Cl H H H OCF₃ H CH H 20N H F H H H CF₃ H CH H 21N H F F H H CF₃ H CH H 22N H Cl H H H CF₃ H CH H 23N H F H H H phenoxy H CH H 24N H CF₃ Cl H H CH₃ H CH H 25N H CF₃ F H H CH₃ H CH H 26N H H H H H CF₃ H CH H 27N F F H H H CF₃ H CH H 28N H H OCH₃ H H CF₃ H CH H 29N H F F H H CH₃ H CH H 30N H OCH₃ H H H CH₃ H CH H 31N H H CH₃ H H H H CH H 32N H Cl H H H H H CH H 33N H F H H H F H CH H 34N H H OCH₃ H H CH₃ H CH H 35N H H H H H H H CH H 36N H H CH₃ H H CH₃ H CH H 37N H H Cl H H H H CH H 38N H F H H H 3-CF₃-phenoxy H CH H 39N H F H H H 4-CH₃O-phenoxy H CH H 40N H F H H H 4-Cl-phenoxy H CH H 41N H F H H H H H CH H 42N H F H H H CH₃ H CH H 43N H F H F H CH₃ H CH H 44N F F H H H CH₃ H CH H 45N H Cl H H H CH₃ H CH H 46N H CH₃ H H H CH₃ H CH H 48N H H CH₃ H H CF₃ H CH H 51N H H CH₃ H H F H CH H 52N H CF₃ H H H F H CH H 53N H CF₃ H H H CH₃ H CH H 54N H OCH₃ H H H CF₃ H CH H 56N H H CH₃ H H CF₃ H CH H 57N H phenoxy H H H H OCF₃ CH H 58N H H H H H H OCF₃ CH H 59N H OCF₃ H H H H OCF₃ CH H 60N H CF₃ F H H H CF₃ CH H 61N H H OCH₃ H H H CF₃ CH H 62N H CH₃ H H H H CF₃ CH H 63N H Cl H H H H CF₃ CH H 64N H CF₃ H H H H OCF₃ CH H 65N H F H H H H OCF₃ CH H 66N H F H F H H OCF₃ CH H 67N H Br H H H H OCF₃ CH H 68N H Cl H H H H OCF₃ CH H 69N H F F H H H OCF₃ CH H 70N H F H H H H phenyl CH H 71N H CH₃ H H H H OCF₃ CH H 72N H F F H H H CF₃ CH H 73N H Cl H H H H CH₃ CH H 74N H OCH₃ H H H H CH₃ CH H 75N H F H H H H CH₃ CH H 76N F F H H H H OCF₃ CH H 78N H H OCH₃ H H H CH₃ CH H 79N H H CH₃ H H H CH₃ CH H 80N H CH₃ H H H H CH₃ CH H 82N H F F H H H CH₃ CH H 83N H F H F H H CH₃ CH H 84N F F H H H H CH₃ CH H 85N F CF₃ H H H H CH₃ CH H 86N H H CH₃ H H H CF₃ CH H 88N H CF₃ H H H H CH₃ CH H 90N H H CF₃ H H H CH₃ CH H 92N H CF₃ F H H H CH₃ CH H

TABLE 4 Structure of “Secondary Phenyl Amine” Reagents (Z is covalent bond; there is no R₁₅ substituent; R₄ and R₁₃ equal H). (XIII-A)

Spacer Rgnt. Bond No. R₅ R₆ R₇ R₈ Y R₁₄ R₉ R₁₀ R₁₁ R₁₂ Spacer Points 93N Br H H CH H H H OCF₃ —O— R₈ + R₉ 94N OCF₃ H H CH H H H OCF₃ — R₈ + R₉ 95N Br H H C H OCF₃ H H ═CH— R₈ + R₁₄ 96N OH OH H H CH H H C₆H₅O H H none none 97N C₆H₅O H H H CH H H OH OH H none none 98N 3-pyridyl H H H CH H H CF₃ H H none none 99N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂ 100N SO₂CH₃ H H H CH H H OCF₃ H H none none 101N C₆H₅O H H H CH H H C₆H₅O H H none none 102N CF₃O H H H CH H H C₆H₅O H H none none 103N C₆H₅ H H H CH H H C₆H₅O H H none none 104N H C₆H₅ H H CH H H C₆H₅O H H none none 105N C₆H₅O H H H CH H H 4-Cl—C₆H₄O H H none none 106N CF₃O H H H CH H H 4-Cl—C₆H₄O H H none none 107N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H H none none 108N CF₃O H H H CH H H 3,4-Cl—C₆H₃O H H none none 109N CF₃O H H H CH H H 3,5-Cl—C₆H₃O H H none none 110N CF₃O H H H CH H H 3-CH₃O— H H none none C₆H₄O 111N CF₃O H H H CH H H H 3-CH₃O— H none none C₆H₄O 112N CF₃O H H H CH H H 3-CF₃—C₆H₄O H H none none 113N CF₃O H H H CH H H C₆H₅—CH₂O H H none none 114N CF₃O H H H CH H H C₆H₅—CH₂O CH₃O H none none 115N CF₃O H H H CH H H C₆H₅—CH₂O C₆H₅— H none none CH₂O 116N CF₃O H H H CH H H ethoxy H H none none 117N CF₃O H H H CH H H CH₃CO₂ H H none none 118N CF₃O H H H CH H H HOCH₂— H H none none CH₂O 119N CF₃O H H H CH H H

H H none none 120N CF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂O H none none 121N CF₃O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H none none 122N CF₃O H H H CH H H CH₃O CH₃O H none none 123N CF₃O H H H CH H H ethoxy CH₃O H none none 124N CF₃O H H H CH H H ethoxy ethoxy H none none 125N CF₃O H H H CH H H CH₃CO₂ CH₃CO₂ H none none 126N CF₃O H H H CH H H CH₃O CH₃CO₂ H none none 127N CF₃O H H H CH H H n-butoxy H H none none 128N CF₃O H H H CH H H CH₃O H H none none 129N CF₃O H H H CH H H H CH₃O H none none 130N CH₃O H H H CH H H CH₃O H H none none 131N CH₃O H H H CH H H H CF₃O H none none 132N CF₃O H H H CH H H H ethoxy H none none 133N CF₃O H H H CH H H H n-propoxy H none none 134N C₆H₅—CH₂O H H H CH H H CF₃O H H none none 135N C₆H₅—CH₂O H H H CH H H C₆H₅O H H none none 136N ethoxy H H H CH H H CF₃O H H none none 137N R₅ + R₆ = OCH₂O H H CH H H CF₃O H H none none 138N R₅ + R₆ = OCH₂O H H CH H H C₆H₅O H H none none 139N R₅ + R₆ = OCH₂CH₂O H H CH H H CF₃O H H none none 140N CH₃O CH₃O H H CH H H CF₃O H H none none 141N R₅ + R₆ = OCH₂CH₂CH₂O H H CH H H CF₃O H H none none 142N cyclo CH₃O H H CH H H CF₃O H H none none pentoxy 143N H C₆H₅O H H CH H H CF₃O H H none none 144N CH₃O CH₃O CH₃O H CH H H CF₃O H H none none 145N H CF₃O H H CH H H CF₃O H H none none 146N H Benzyl H H CH H H CF₃O H H none none 147N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCH₂CH₂O H none none 148N H CF₃O H H CH H H CF₃ H H none none 149N C₆H₅O H H H CH H H CF₃ H H none none 150N C₆H₅ H H H CH H H CF₃ H H none none 151N H C₆H₅ H H CH H H CF₃ H H none none 152N CN H H H CH H H CF₃ H H none none 153N H OCF₃ H H CH H H CF₃ H H none none 154N OCF₃ H H H CH H H H CF₃ H none none 155N C₆H₅O H H H CH H H H CF₃ H none none 156N C₆H₅ H H H CH H H H CF₃ H none none 157N H C₆H₅ H H CH H H H CF₃ H none none 158N CN H H H CH H H H CF₃ H none none 159N OCF₃ H H H CH H H H CF₃ H none none 160N CF₃ H H H CH H H H C₆H₅ H none none 161N CF₃ H H H CH H H 3-CF₃— H H none none C₆H₅O 162N CF₃ H H H CH H H C₆H₅O H H none none 163N CF₃ H H H CH H H CF₃O H H none none 164N H CF₃ H H CH H H H C₆H₅ H none none 165N H CF₃ H H CH H H 3-CF₃— H H none none C₆H₅O 166N H CF₃ H H CH H H CF₃O H H none none 167N H CF₃ H H CH H H C₆H₅O H H none none 168N CF₃ H CF₃ H CH H H CF₃O H H none none 169N CF₃ H CF₃ H CH H H C₆H₅O H H none none 170N CF₃O H H H CH H H CF₃ H CF₃ none none 171N C₆H₅O H H H CH H H CF₃ H CF₃ none none 172N H C₆H₅O H H CH H H C₆H₅O H H none none 173N H CF₃O H H CH H H CF₃O H H none none 174N H CF₃O H H CH H H H C₆H₅O H none none 175N C₆H₅O H H H CH H H H C₆H₅O H none none 176N H C₆H₅O H H CH H H H OCF₃ H none none 177N H C₆H₅O H H CH H H H C₆H₅O H none none 178N C₆H₅O H H H CH H H H CN H none none 179N C₆H₅O H H H CH H H CN H H none none 180N C₆H₅O H H H CH H H NO₂ H H none none 181N C₆H₅O H H H CH H H H NO₂ H none none 182N C₆H₅O H H H CH H H H SO₂CH₃ H none none 183N C₆H₅O H H H CH H H H 2-NO₂-4- H none none Cl—C₆H₃O 184N C₆H₅O H H H CH H H 4-Cl—C₆H₄O H H none none 185N C₆H₅O H H H CH H H 3,4-Cl—C₆H₃O H H none none 186N C₆H₅O H H H CH H H 3-CF₃— H H none none C₆H₃O 187N C₆H₅O H H H CH H H 3,5-Cl—C₆H₃O H H none none 188N C₆H₅O H H H CH H H H CH₃O H none none 189N C₆H₅O H H H CH H H H CO₂CH₃ H none none 190N C₆H₅O H H H CH H H 3-CH₃O H H none none C₆H₅O 191N C₆H₅O H H H CH H H 4-CH₃O H H none none C₆H₅O 193N C₆H₅O H H H CH H H CO₂CH₃ H H none none 194N CN H H H CH H H OCF₃ H H none none 195N NO₂ H H H CH H H OCF₃ H H none none 196N H CN H H CH H H OCF₃ H H none none 197N H NO₂ H H CH H H OCF₃ H H none none 198N SO₂CH₃ H H H CH H H OCF₃ H H none none 199N H SO₂CH₃ H H CH H H OCF₃ H H none none 200N H 4-F—C₆H₅ H H CH H H OCF₃ H H none none SO₂ 201N SO₂N H H H CH H H OCF₃ H H none none (CH₃)₂ 202N H SO₂N H H CH H H OCF₃ H H none none (CH₃)₂ 203N H CONH₂ H H CH H H OCF₃ H H none none 204N H CONH— H H CH H H OCF₃ H H none none C₆H₅ 205N H CO₂CH₃ H H CH H H OCF₃ H H none none 206N H CO₂C₄H₉ H H CH H H OCF₃ H H none none 207N H 4-Cl—C₆H₅ H H CH H H C₆H₅O H H none none 208N H 4-CF₃O— H H CH H H CF₃O H H none none C₆H₅ 209N 4-F—C₆H₄O H H H CH H H CF₃O H H none none 210N C₆F₅O H H H CH H H CF₃O H H none none 211N H 4-F—C₆H₅ H H CH H H CF₃O H H none none 212N H 4-CN—C₆H₅ H H CH H H CF₃O H H none none 213N H 4-C₆H₅— H H CH H H CF₃O H H none none C₆H₅ 214N C₆H₅O H H H CH CH₃ H CF₃O H H none none 215N C₆H₅O H H H CH CH₃ H NO₂ H H none none 216N C₆H₅O H H H CH CH₃ H H CN H none none 217N C₆H₅O H H H CH 3-CF₃ H CF₃ H H none none C₆H₅ 218N C₆H₅O H H H CH C₆H₅ H H C₆H₅ H none none 219N C₆H₅O H H H CH C₆H₅ H CF₃ H H none none 220N C₆H₅O H H H CH CH₃ H F H H none none 221N C₆H₅O H H H CH CF₃ H H H H none none 222N bond to —O— of R₆ aryl group

H H CH H H CF₃O H H none none 223N to CH₂ of R₆ aryl group

H H CH H H CF₃O H H none none 224N C₆H₅O H H H CH H H OCH₂CF₂H H H none none 225N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 226N 4-F—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 227N 3,4-Cl— H H H CH H H OCF₂CF₂H H H none none C₆H₅O 228N H C₆H₅ H H CH H H OCF₂CF₂H H H none none 229N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₂H H H none none 230N H 4-F—C₆H₅ H H CH H H OCF₂CF₂H H H none none 231N H 4-Br—C₆H₅ H H CH H H OCF₂CF₂H H H none none 232N 4-Br—C₆H₅O H H H CH H H OCF₂CF₂H H H none none 233N C₆H₅O H H H CH H H OCF₂CF₃ H H none none 234N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 235N 4-F—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 236N 3,4-Cl— H H H CH H H OCF₂CF₃ H H none none C₆H₅O 237N H C₆H₅ H H CH H H OCF₂CF₃ H H none none 238N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₃ H H none none 239N H 4-F—C₆H₅ H H CH H H OCF₂CF₃ H H none none 240N H 4-Br—C₆H₅ H H CH H H OCF₂CF₃ H H none none 241N 4-Br—C₆H₅O H H H CH H H OCF₂CF₃ H H none none 242N C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 243N 4-Cl—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 244N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 245N 3,4-Cl— H H H CH H H OCCl₂CCl₂H H H none none C₆H₅O 246N H C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 247N H 4-Cl—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 248N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 249N H 4-Br—C₆H₅ H H CH H H OCCl₂CCl₂H H H none none 250N 4-Br—C₆H₅O H H H CH H H OCCl₂CCl₂H H H none none 251N C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 252N 4-Cl—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 253N 4-F—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 254N 3,4-Cl— H H H CH H H OCCl₂CCl₃ H H none none C₆H₅O 255N H C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 256N H 4-Cl—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 257N H 4-F—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 258N H 4-Br—C₆H₅ H H CH H H OCCl₂CCl₃ H H none none 259N 4-Br—C₆H₅O H H H CH H H OCCl₂CCl₃ H H none none 260N C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 261N 4-Cl—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 262N 4-F—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 263N 3,4-Cl— H H H CH H H OCCl₂CF₃ H H none none C₆H₅O 264N H C₆H₅ H H CH H R OCCl₂CF₃ H H none none 265N H 4-Cl—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 266N H 4-F—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 267N H 4-Br—C₆H₅ H H CH H H OCCl₂CF₃ H H none none 268N 4-Br—C₆H₅O H H H CH H H OCCl₂CF₃ H H none none 269N C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 270N 4-Cl—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 271N 4-F—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 272N 3,4-Cl— H H H CH H H OCF₂CCl₃ H H none none C₆H₅O 273N H C₆H₅ H H CH H H OCF₂CCl₃ H H none none 274N H 4-Cl—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 275N H 4-F—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 276N H 4-Br—C₆H₅ H H CH H H OCF₂CCl₃ H H none none 277N 4-Br—C₆H₅O H H H CH H H OCF₂CCl₃ H H none none 278N C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 279N 4-Cl—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 280N 4-F—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 281N 3,4-Cl— H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none C₆H₅O 282N H C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 283N H 4-Cl—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 284N H 4-F—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 285N H 4-Br—C₆H₅ H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 286N 4-Br—C₆H₅O H H H CH H H OCF₂CF₂H OCF₂CF₂H H none none 287N C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 288N 4-Cl—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 289N 4-F—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 290N 3,4-Cl— H H H CH H H OCF₃ OCF₃ H none none C₆H₅O 291N H C₆H₅ H H CH H H OCF₃ OCF₃ H none none 292N H 4-Cl—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 293N H 4-F—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 294N H 4-Br—C₆H₅ H H CH H H OCF₃ OCF₃ H none none 295N 4-Br—C₆H₅O H H H CH H H OCF₃ OCF₃ H none none 296N C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 297N 4-Cl—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 298N 4-F—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 299N 3,4-Cl— H H H CH H H OCF₂H OCF₂H H none none C₆H₅O 300N H C₆H₅ H H CH H H OCF₂H OCF₂H H none none 301N H 4-Cl—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 302N H 4-F—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 303N H 4-Br—C₆H₅ H H CH H H OCF₂H OCF₂H H none none 304N 4-Br—C₆H₅O H H H CH H H OCF₂H OCF₂H H none none 305N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 306N 4-Cl—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 307N 4-F—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 308N 3,4-Cl— H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none C₆H₅O 309N H C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 310N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 311N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 312N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 313N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCF₂CF₂O H none none 314N C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 315N 4-Cl—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 316N 4-F—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 317N 3,4-Cl— H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none C₆H₅O 318N H C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 319N H 4-Cl—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 320N H 4-F—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 321N H 4-Br—C₆H₅ H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 322N 4-Br—C₆H₅O H H H CH H H R₁₀ + R₁₁ = OCCl₂CCl₂O H none none 323N H H H H CH H H OH H H none none 324N H H H H CH H H OH OH H none none 325N H H H H CH H H H OH H none none 326N H H H H CH H H OCH₂CF₃ H H none none 327N H H H H CH H H H OCH₂CF₃ H none none 328N H H H H CH H H OCH₂CF₂CF₃ H H none none 329N H H H H CH H H OCH₂CH₂CF₃ H H none none 330N H H H H CH H H OCH(CF₃)₃ H H none none 331N H 4-F—C₆H₅O H H CH H H H H H none none 332N 4-F—C₆H₅O H H H CH H H H H H none none 333N H cyclo- H H CH H H H H H none none hexoxy 334N cyclo-hexoxy H H H CH H H H H H none none 335N H C(CH₃)₃ H H CH H H H H H none none 336N F H H H CH H H

bond to indicated phenyl carbon of R₁₀ subst. H none none

TABLE 5 Structure of “Secondary Phenyl Amine” Reagents (Y and Z each equal CH; R₇, R₈, R₁₂, R₁₃, R₁₄, and R₁₅ each equal H). (XIII-A)

Reagent Number R₄ R₅ R₆ R₉ R₁₀ R₁₁ 1DB H OCF₃ H H OCF₃ H 2DB H Cl H H H CF₃ 3DB H Br H H OCF₃ H 4DB H Cl H H OCF₃ H 5DB H Cl H H CF₃ H 6DB H H Cl H CF₃ H 7DB H F H H OCF₃ H 8DB H H Cl H H CF₃ 9DB H F H H H CF₃ 10DB H H F H H CF₃ 11DB F H H H H CF₃ 12DB H Cl H CF₃ H H 13DB H H Cl CF₃ H H 14DB Cl H H CF₃ H H 15DB H F H CH₃ H H 16DB H H F H H CH₃ 17DB H F H H CH₃ H 18DB F H H CH₃ H H 19DB H H F H CH₃ H 20DB F H H H H CH₃ 21DB F H H H CF₃ H 22DB Cl H H H CF₃ H 23DB H F H CF₃ H H 24DB H H F CF₃ H H 25DB H F H H CF₃ H 26DB H H F H CF₃ H 27DB H OCF₃ H H H OCF₃

As summarized in the general Scheme 1 and specific descriptions above, Schemes 3, 4, 9, and 10 illustrate the principles of Scheme 1 for the preparation of specifically substituted “Secondary Heteroaryl Amines” (XIIIA-H) having 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups and “Secondary Phenyl Amines” (XIII-A) having two aryl groups.

Synthetic Scheme 2 shows the preparation of the class of compounds of the present invention corresponding to Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated l-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) wherein A and Q are independently aryl and heteroaryl.

Derivatives of “Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”, “Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”, “Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”, “Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”, and “Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”, wherein A and Q are independently aryl and heteroaryl, in which the hetero atom (—O—) is attached to an alkyl group removed from the amine by three or more carbons are readily prepared by anion chemistry using Method B of Scheme 2. The anion of “Generic Secondary Amine” amines, hydroxylamines, and hydrazines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between −78 and 0° C., preferrably between −78 and 60° C. and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between −78 and 0° C., preferrably between −78 and −60° C., with suitable cooling, an appropriate alkyl halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyl triflate or similar alkylating reagent of the general structure:

where M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate, X is oxy, and XXX is a chiral reagent in the indicated (R)-configuration. After allowing the reaction mixture to warm to room temperature, the reaction product is added to water, neutralized if necessary, and extracted with a water-immiscible solvent such as diethyl ether or methylene chloride. The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedaino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), wherein A and Q are independently aryl and heteroaryl. This material is purified, for example, by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”). Products are tested for purity by HPLC. If necessary, Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propahols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific compounds prepared are summarized in Tables 6 and 7.

Compounds of Formula (XXX), which can be used to prepare the “Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanol” compounds of Tables 6 and 7, are given in Table 2. Reagents 1a and 2a in Table 2 are prepared from the corresponding alcohols. (R)-Chiral alcohol precursors to 1a, 2a, and similiar alcohols that can be envisioned by one of inventive skill can be obtained from the corresponding racemic mixture of the R-enatiomer and S-enantiomer by separation procedures using preparative gas chromatography and high pressure liquid chromatography using chiral chromatographic columns. The tosylates of chiral alcohols and racemic mixtures are readily obtained by reacting the corresponding alcohol with tosyl chloride using procedures found in House's Modern Synthetic Reactions, Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons, which are incorporated herein by reference.

TABLE 6 Structure of Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols (Y is CH; R₈, R₉, R₁₂, R₁₃, and R₁₄ are each H; Z is covalent bond and R₁₅ is absent).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n R₂ R₃ R₄ R₅ R₆ R₇ R₁₀ R₁₁ 1A 1N CF₃ 3 H H H C₆H₅O H H OCF₂CF₂H H 1A 2N CF₃ 3 H H H OCF₃ H H OCF₂CF₂H H 1A 3N CF₃ 3 H H F H H F OCF₂CF₂H H 1A 4N CF₃ 3 H H H F H H OCF₂CF₂H H 1A 5N CF₃ 3 H H H C₆H₅O H H OCF₃ H 1A 6N CF₃ 3 H H H OCF₃ H H OCF₃ H 1A 7N CF₃ 3 H H H H phenyl H OCF₃ H 1A 8N CF₃ 3 H H H phenyl H H OCF₃ H 1A 9N CF₃ 3 H H H H H H OCF₃ H 1A 10N CF₃ 3 H H H Br H H OCF₃ H 1A 11N CF₃ 3 H H H CF₃ F H CF₃ H 1A 12N CF₃ 3 H H H CH₃ H H CF₃ H 1A 13N CF₃ 3 H H H CF₃ H H CF₃ H 1A 14N CF₃ 3 H H H CH₃ H H OCF₃ H 1A 15N CF₃ 3 H H H F F H OCF₃ H 1A 16N CF₃ 3 H H H Br H H CF₃ H 1A 17N CF₃ 3 H H H CF₃ F H OCF₃ H 1A 18N CF₃ 3 H H H F H H OCF₃ H 1A 19N CF₃ 3 H H H Cl H H OCF₃ H 1A 20N CF₃ 3 H H H F H H CF₃ H 1A 21N CF₃ 3 H H H F F H CF₃ H 1A 22N CF₃ 3 H H H Cl H H CF₃ H 1A 23N CF₃ 3 H H H F H H phenoxy H 1A 24N CF₃ 3 H H H CF₃ Cl H CH₃ H 1A 25N CF₃ 3 H H H CF₃ F H CH₃ H 1A 26N CF₃ 3 H H H H H H CF₃ H 1A 27N CF₃ 3 H H F F H H CF₃ H 1A 28N CF₃ 3 H H H H OCH₃ H CF₃ H 1A 29N CF₃ 3 H H H F F H CH₃ H 1A 30N CF₃ 3 H H H OCH₃ H H CH₃ H 1A 31N CF₃ 3 H H H H CH₃ H H H 1A 32N CF₃ 3 H H H Cl H H H H 1A 33N CF₃ 3 H H H F H H F H 1A 34N CF₃ 3 H H H H OCH₃ H CH₃ H 1A 35N CF₃ 3 H H H H H H H H 1A 36N CF₃ 3 H H H H CH₃ H CH₃ H 1A 37N CF₃ 3 H H H H Cl H H H 1A 38N CF₃ 3 H H H F H H 3-CF₃- H phenoxy 1A 39N CF₃ 3 H H H F H H 4-CH₃O- H phenoxy 1A 40N CF₃ 3 H H H F H H 4-Cl- H phenoxy 1A 41N CF₃ 3 H H H F H H H H 1A 42N CF₃ 3 H H H F H H CH₃ H 1A 43N CF₃ 3 H H H F H F CH₃ H 1A 44N CF₃ 3 H H F F H H CH₃ H 1A 45N CF₃ 3 H H H Cl H H CH₃ H 1A 46N CF₃ 3 H H H CH₃ H H CH₃ H 1A 48N CF₃ 3 H H H H CH₃ H CF₃ H 1A 51N CF₃ 3 H H H H CH₃ H F H 1A 52N CF₃ 3 H H H CF₃ H H F H 1A 53N CF₃ 3 H H H CF₃ H H CH₃ H 1A 54N CF₃ 3 H H H OCH₃ H H CF₃ H 1A 56N CF₃ 3 H H H H CH₃ H CF₃ H 1A 57N CF₃ 3 H H H C₆H₅O H H H OCF₃ 1A 58N CF₃ 3 H H H H H H H OCF₃ 1A 59N CF₃ 3 H H H OCF₃ H H H OCF₃ 1A 60N CF₃ 3 H H H CF₃ F H H CF₃ 1A 61N CF₃ 3 H H H H OCH₃ H H CF₃ 1A 62N CF₃ 3 H H H CH₃ H H H CF₃ 1A 63N CF₃ 3 H H H Cl H H H CF₃ 1A 64N CF₃ 3 H H H CF₃ H H H OCF₃ 1A 65N CF₃ 3 H H H F H H H OCF₃ 1A 66N CF₃ 3 H H H F H F H OCF₃ 1A 67N CF₃ 3 H H H Br H H H OCF₃ 1A 68N CF₃ 3 H H H Cl H H H OCF₃ 1A 69N CF₃ 3 H H H F F H H OCF₃ 1A 70N CF₃ 3 H H H F H H H phenyl 1A 71N CF₃ 3 H H H CH₃ H H H OCF₃ 1A 72N CF₃ 3 H H H F F H H CF₃ 1A 73N CF₃ 3 H H H Cl H H H CH₃ 1A 74N CF₃ 3 H H H OCH₃ H H H CH₃ 1A 75N CF₃ 3 H H H F H H H CH₃ 1A 76N CF₃ 3 H H F F H H H OCF₃ 1A 78N CF₃ 3 H H H H OCH₃ H H CH₃ 1A 79N CF₃ 3 H H H H CH₃ H H CH₃ 1A 80N CF₃ 3 H H H CH₃ H H H CH₃ 1A 82N CF₃ 3 H H H F F H H CH₃ 1A 83N CF₃ 3 H H H F H F H CH₃ 1A 84N CF₃ 3 H H F F H H H CH₃ 1A 85N CF₃ 3 H H F CF₃ H H H CH₃ 1A 86N CF₃ 3 H H H H CH₃ H H CF₃ 1A 88N CF₃ 3 H H H CF₃ H H H CH₃ 1A 90N CF₃ 3 H H H H CF₃ H H CH₃ 1A 92N CF₃ 3 H H H CF₃ F H H CH₃

TABLE 7 Structure of Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols (Y and Z are each CH; R₈, R₉, R₁₂, R₁₃, R₁₄ and R₁₅ are each H).

Inhibitor Number Column 1 + Column 2 Reagent Reagent R₁ n R₂ R₃ R₄ R₅ R₆ R₉ R₁₀ R₁₁ 1A 1DB CF₃ 3 H H H OCF₃ H H OCF₃ H 1A 2DB CF₃ 3 H H H Cl H H H CF₃ 1A 3DB CF₃ 3 H H H Br H H OCF₃ H 1A 4DB CF₃ 3 H H H Cl H H OCF₃ H 1A 5DB CF₃ 3 H H H Cl H H CF₃ H 1A 6DB CF₃ 3 H H H H Cl H CF₃ H 1A 7DB CF₃ 3 H H H F H H OCF₃ H 1A 8DB CF₃ 3 H H H H Cl H H CF₃ 1A 9DB CF₃ 3 H H H F H H H CF₃ 1A 10DB CF₃ 3 H H H H F H H CF₃ 1A 11DB CF₃ 3 H H F H H H H CF₃ 1A 12DB CF₃ 3 H H H Cl H CF₃ H H 1A 13DB CF₃ 3 H H H H Cl CF₃ H H 1A 14DB CF₃ 3 H H Cl H H CF₃ H H 1A 15DB CF₃ 3 H H H F H CH₃ H H 1A 16DB CF₃ 3 H H H H F H H CH₃ 1A 17DB CF₃ 3 H H H F H H CH₃ H 1A 18DB CF₃ 3 H H F H H CH₃ H H 1A 19DB CF₃ 3 H H H H F H CH₃ H 1A 20DB CF₃ 3 H H F H H H H CH₃ 1A 21DB CF₃ 3 H H F H H H CF₃ H 1A 22DB CF₃ 3 H H Cl H H H CF₃ H 1A 23DB CF₃ 3 H H H F H CF₃ H H 1A 24DB CF₃ 3 H H H H F CF₃ H H 1A 25DB CF₃ 3 H H H F H H CF₃ H 1A 26DB CF₃ 3 H H H H F H CF₃ H 1A 27DB CF₃ 3 H H H OCF₃ H H H OCF₃

Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds can also be prepared using Method B of Scheme 2 through the use of racemic (XXX) as described followed by preparative separation of the R-enantiomer from the S-enatiomer using chiral chromatographic procedures such as preparative gas chromatography and high pressure liquid chromatography using readily available chiral chromatographic columns and procedures.

A preferred procedure for Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds is the novel inventive Method A of Scheme 2. (R)-Chiral oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds are prepared by reacting “Generic Secondary Amine” amines, hydroxylamines, and hydrazines of Formula XIII with (R)-chiral oxiranes of the type listed in Table 1 and represented by the general structure:

Oxiranes having a specific stereochemical arrangement of R₁, R₂ and R₃ can be prepared using chiral procedures such as those published in 1995 by Ramachandran, Gong, and Brown in the Journal of Organic Chemistry, Vol. 60, pages 41 to 46; cited references also detail alternate procedures to prepare chiral and achiral epoxides, which are incorporated herein by reference. For example, the specific preparation of R-(+)-1,1,1-trifluoro-2,3-epoxypropane,

using a procedure adopted from H. C. Brown et al. (J. Org. Chem. 60, 41-46, (1995)), is accomplished as described in Example 4. Many of the epoxides summarized in Table 1 can be prepared in the (R)-configuration using procedures analogous to that given above for R-(+)-1,1,1-trifluoro-2,3-epoxypropane.

In some cases, achiral oxiranes of (XX) can be prepared from the corresponding alkenes by reaction of epoxidation reagents such as meta-chloroperbenzoic acid (MCPBA) and similar type reagents readily selectable by a person of skill-in-the-art with alkenes. Fieser and Fieser in Reagents for Organic Synthesis, John Wiley & Sons provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are incorporated herein by reference. These achiral oxiranes can be reacted in an identical manner to that described for (R)-chiral oxiranes with “Generic Secondary Amine” amines, hydroxylamines, and hydrazines of Formula XIII to afford racemic compounds structurally identical to those of Formula I-HP, Formula I-HPC, and Formula I-C but with the corresponding (S) chiral configuration present in an equivalent amount. Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds can be obtained by preparative chiral chromatography of said racemic mixtures to obtain the (R)-chiral configuration of Formula I-HP, Formula I-HPC, and Formula I-CP substantially free of the (S)-chiral configuration enantiomer. Alternatively, achiral oxiranes may be separated by chiral preparative chromatography into their respective (R)-Chiral and (S)-Chiral enantiomers and the (R)-Chiral enantiomer reacted to afford Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds.

A mixture of a “Generic Secondary Amine” amine, hydroxylamine, or hydrazine of Formula XIII and an excess of a halogenated oxirane of (R)-chiral configuration of Formula XX are stirred and heated to 40-90° C. for 5 to 48 hours in a tightly capped or contained reaction vessel. More preferrably, a Lewis acid such as a transition metal-based salts (for example, ytterbium triflate, hafnium triflate, scandium triflate, neodynium triflate, gadolium triflate, and zirconium triflate) in methylene chloride, tetrahydrofuran, or, more preferrably, acetonitrile is added to speed up the reaction to a total time of 4 to 18 hours, improve yields, to permit the reaction temperature to be reduced to 15-65° C., and to use a smaller excess of halogenated oxirane. When a Lewis acid is used, the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas. After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane). The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO₄ and concentrated in vacuo to yield crude Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds. This material is purified by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds. Products are tested for purity by HPLC. If necessary, the Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds are purified by additional chromatography or recrystallization, Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds prepared are summarized in the Examples 1 through 44, and Example Tables 1 through 12.

TABLE 1 Structure of (R)-Chiral Oxirane Reagents. (XX)

Reagent Number R₁ R₂ R₃ 1 CF₃ H H 2 CCl₃ H H 3 CF₃ CH₃ H 4 CF₃CF₂ H H 5 CF₃CF₂CF₂ H H 6 CF₃OCF₂CF₂ H H 7 CF₃CH₂ H H 9 CF₃ H CF₃ 11 CF₃ C₆H₅ H 12 CCl₃ C₆H₅ H 13 CCl₃ Cyclopropyl H 14 CCl₃ CH₃ H 15 CCl₃ (CH₃)₂CH H 16 CHCl₂ H H 18 CF₃ H CH₃ 27 CCl₃CH₂ H H 28 CBr₃CH₂ H H 29 CHBr₂CH₂ H H 30 CBrCl₂ H H 31 CClF₂ H H 32 CCl₂F H H 33 CCl₃CCl₂ H H 43 FCH₂ H H 56 CBrF₂CClFCH₂ H H 57 HCF₂CF₂OCH₂ H H

TABLE 2 Structure and Source of Alcohol and Glycol Reagents. (XXX)

Reagent Number R₁ n M R₂ R₃ X—R₁₆ Source of Reagent 1A CF₃ 3 OTs H H OH Chiral separation and then tosylation of alcohol from Justus Liebigs Ann. Chem. (1969), 720, 81-97. 2A CF₃CH₂CH₂ 3 OTs H H OH Chiral separation and then tosylation of alcohol from Z. Naturforsch., B: Chem. Sci. (1997), 52 (3). 413-418

As summarized in the general Scheme 2 and specific descriptions above, Schemes 5,6,7, and 11 illustrate the principles of Scheme 2 for the preparation of specifically substituted Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) having 2 aryl groups, Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”) having two aromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups, and Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) having two aromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups.

Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedarnino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7 and 9 to 11. Schemes 45 to 50 detail such procedures to prepare aminopropanol compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XVL (“Generic Substituted Alkylamine”). Said halogenated, oxygen containing primary alkylamine XVL, formed in Schemes 45 and 48, is itself converted to secondary amines, VLX-H (“Heteroaryl Alkyl Amine) and VLX (“Phenyl Alkyl Amine”), using procedures disclosed above. Primary alkylamine XVL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (“Heteroaryl Carbonyl”) and XI-A (“Phenyl Carbonyl”) with azeotropic distillation to form imines, VL-H (“Heteroaryl Imine”) and VL (“Phenyl Imine”). Said imines VL-H and VL are then reduced with or without prior isolation by Reduction Methods 1,2 or 3 as disclosed above and in Schemes 1,3, and 9 to yield secondary amines, VLX-H (“Heteroaryl Alkyl Amine) and VLX (“Phenyl Alkyl Amine”). Said secondary amine VLX-H can be converted according to Schemes 46 and 47 to give Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”) and Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds. Using Schemes 49 and 50, VLX can be converted to Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds. Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX-H with an aralkyl bromide or aryl bromide instead of using an heteroaralkyl bromide or heteroaryl bromide as described in Schemes 46 and 47. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX with an heteroaryl bromide or heteroaralkyl bromide instead of using an aryl bromide or an aralkyl bromide as described in Schemes 49 and 50.

Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7,9 to 11, and 45 to 50. Schemes 56,57, and 58 detail alternate procedures to prepare (R)-Chiral Halogenated 1-Substitutedamino-2-propanols” compounds of the present invention by initial formation of an halogenated, oxygen containing secondary alkylamines VLX and VLXX (“Phenyl Alkylamines”) and VLXX-O (“Phenyl Oxy Alkylamines”). Said secondary alkylamines VLX and VLXX (“Phenyl Alkylamines”) and VLXX-O (“Phenyl Oxy Alkylamines”) can be converted according to Schemes 56,57, and 58 to Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with appropriate aromatic halides such as aryl bromides and heteroaryl bromides as desired.

Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7,9 through 11,45 through 50, and 56 through 58. Another alternate procedure to prepare “(R)-Chiral Halogenated 1-Substitutedamino-2-propanols” compounds of the present invention can be achieved by reacting secondary amines of Formula XIIIA-H (“Secondary Heteroaryl Amines”) and Formula XIII-A (“Secondary Phenyl Amines”) with certain cyclic sulfates. Cyclic sulfates useful in the preparation of “(R)-Chiral Halogenated 1-Substitutedamino-2-propanols” compounds of Formulas I-HP, J-HPC, and I-CP have a halogenated or haloalkoxy carbon adjacent to the cyclic sulfate. Some cyclic sulfates useful for the preparation of “(R)-Chiral Halogenated 1-Substitutedamino-2-propanols” compounds of Formulas I-HP, I-HPC, and I-CP have been described by K. P. M. Vanhessche and K. B. Sharpless in Chem. Eur. J, 1997, Vol. 3, No. 4, pages 517-522 and references cited therein. (2R)-(+)-3,3,3-Trifluoro-1,2-propanediol can be prepared as described in the reference cited immediately above from 3,3,3-trifluoropropene followed by separation from the predominating (2S)-(−)-3,3,3-trifluoro-1,2-propanediol. Alternatively, (2R)-(+)-3,3,3-Trifluoro-1,2-propanediol can be prepared by hydrolysis of (2R)-(+)-3,3,3-Trifluoro-2,3-epxoypropane analogous to the procedure described by described by McBee and Burton in J. Am. Chem. Soc., 1952, Vol. 74, page 3022. (2R)-(+)-3,3,3-Trifluoro-1,2-propanediol is converted by reaction with a slight excess of sulfuryl chloride in the presence of 2.5 molar equivalents of imidazole, methylene chloride solvent, and at a temperature of −20° C. to give the desired (4R)(+)-4-trifluoromethyl-2,2-dioxo-1,3,2-dioxathiolane. Reaction of other (R)-Chiral haloalkyl or haloalkoxyalkyl substituted 1,2-ethanediols can afford the corresponding (4R)-substituted-2,2-dioxo-1,3,2-dioxathiolanes. Reaction of (4R)-(+)4-trifluoromethyl-2,2-1,3,2-dioxathiolane or another (4R)-substituted-2,2-dioxo-1,3,2-dioxathiolane with a secondary amine of Formula XIIIA-H (“Secondary Heteroaryl Amines”) and Formula XIII-A (“Secondary Phenyl Amines”) in an anhydrous polar, non-protic solvent such as tetrahydrofuran or acetonitrile at 25-60° C. until the reaction is complete can afford the mono-sulfate ester of a compound of Formulas I-HP, I-HPC, and I-CP. Removal of the solvent followed by addition of diethyl ether and excess 20% aqueous sulfuric acid can lead to a precipitant of the crude mono-sulfate ester of a compound of Formulas I-HP, I-HPC, and I-CP. This precipitant can be filtered, the solid can be washed with ether, it can be resuspended in aqueous 20% sulfuric acid, and can be heated to 80-95° C. to give an aqueous solution of the sulfate salt of crude a compound of Formulas I-HP, I-HPC, and I-CP. Neutralization of the aqueous solution, extraction with a water immiscible solvent such as diethyl ether or methylene chloride, drying the organic solvent over anhydrous magnesium sulfate, and removal of solvent can afford a compound of Formulas I-HP, I-HPC, and I-CP. Compounds of Formulas I-HP, I-HPC, and I-CP can be purified as described previously. By using a wide variety of (R)-Chiral diols, secondary amines of Formula XIIIA-H (“Secondary Heteroaryl Amines”) and Formula XIII-A (“Secondary Phenyl Amines”), and reaction conditions described herein, a large variety of compounds of Formulas I-HP, I-HPC, and I-CP may be preparable.

Formula I-H (“Generic Polycyclic Aryl and Heteroaiyl (R)-Chiral Halogenated 1-Substitutedamino(n+1)-alkanols”) and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), in which the halogenated hydroxy containing alkyl side chain has three carbons between the amine and hydroxy group, can be prepared in a manner similar to procedures disclosed above and in Schemes 45 to 50. Schemes 30 to 35 detail such procedures to prepare 1-amino-3-butanol compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL (“Generic Substituted Alkylamine”). Said halogenated, oxygen containing primary alkylamine XL, formed in Schemes 30 and 33, is itself converted to secondary amines, LX-H (“Heteroaryl Alkyl Amine) and LX (“Phenyl Alkyl Amine”), using procedures disclosed above. Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (“Heteroaryl Carbonyl”) and XI-A (“Phenyl Carbonyl”) with azeotropic distillation to form imines, L-H (“Heteroaryl Imine”) and L (“Phenyl Imine”). Said imines L1H and L are then reduced with or without prior isolation by Reduction Methods 1,2 or 3 as disclosed above and in Schemes 1,3, and 9 to yield secondary amines, LX-H (“Heteroaryl Alkyl Amine) and LX (“Phenyl Alkyl Amine”). Said secondary amine LX-H can be converted according to Schemes 31 and 32 to Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”). Using Schemes 34 and 35, LX can be converted to Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”). Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting LX-H with an aryl bromide instead of using an heteroaryl bromide as described in Schemes 31 and 32. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting LX with an heteroaryl bromide instead of using an aryl bromide as described in Schemes 34 and 35.

Particularly useful procedures to prepare Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds of the present invention in which the heteroaryl group is directly bonded is disclosed in Schemes 51 to 54. An halogenated, hydroxy containing primary alkylamine XVL (“Generic Substituted Alkylamine”) formed in Schemes 45 and 48 is itself converted by reaction with LXXI-AH (“Heteroaryl Halide”) to afford secondary amine VLXX-H (“Heteroaryl Secondary Amine) using procedures disclosed in Scheme 51 and above. VLXX-H is converted to Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by alkylation chemistry with an aralkyl bromide or aralkyloxyalkyl bromide using either of two procedures disclosed in Scheme 52. Isolation and purification is effected as disclosed previously. An halogenated, hydroxy containing primary alkylamine XL (“Generic Substituted Alkylamine”) formed in Schemes 30 and 33 is itself also converted by reaction with LXXI-AH (“Heteroaryl Halide”) to afford secondary amine LXX-H (“Heteroaryl Secondary Amine) using procedures disclosed in Scheme 53 and above. LXX-H is converted to Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”) and Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”) compounds by alkylation chemistry disclosed in Scheme 54 and previously and as given above with reference to Scheme 52. Isolation and purification of I-H and I-C are effected as disclosed previously.

Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Genetic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds can themselves serve as intermediates for conversion to additional compounds of this invention. Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC and others of the present invention useful as intermediates include those in which the R₇ position substituent in Formulas I-H, I-HP, I-C, I-CP, and I-HPC is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxycarbonyl or other alkoxy carbonyl groups, cyano group, or acyl group. Other preferred compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC and the present invention useful as intermediates include those in which the R₁₀ position substituent is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC and the present invention useful as intermediates include those in which one or more of R₆, R₇, R₁₁, and R₁₂ substituents in Formula VII is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.

Scheme 8 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with a phenol to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Phenoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 12 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula I-HP and I-HPC (“Polycyclic 3-Bromophenyl amd 3-Bromoheteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) by reaction with a phenol or thiophenol to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-HP and I-HPC (“Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, 3-Aryloxyheteroaryl, 3-Arylthioaryl, 3-Heteroarylthioaryl, 3-Heteroarylthioheteroaryl, and 3-Arylthioheteroaryl Aryl amd Heteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 22 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an aryl borinate or an aryl tin to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Arylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 23 discloses the conversion of a 3-bromo substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with a primary or secondary amine to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-R₂₂aminophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 40 discloses the conversion of a 3-bromo substituent at the R₁₀ position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Arylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 41 discloses the conversion of a 3-bromo substituent at the R10 position in Formula I-CP (“Polycyclic 3-Bromophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with a heteroaryl dibutyl tin compound to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Heteroarylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 21 discloses the conversion of a 3-bromomethyl substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Bromomethylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Arylmethylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 13 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula I-HP and I-HPC (“Polycyclic 3-Hydroxyphenyl amd 3-Hydroxyheteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) by reaction with an aryl bromide or heteroaryl bromide to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-HP and I-HPC (“Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 14 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Hyroxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an aryl bromide to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Phenoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 15 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula I-HP and I-HPC (“Polycyclic 3-Hydroxyphenyl amd 3-Hydroxyheteroaryl/Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an aralkyl bromide or heteroaralkyl bromide to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-HP and I-HPC (“Polycyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 16 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Hyroxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an aralkyl bromide to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Aralkyloxyaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 20 discloses the conversion of a 3-hydroxyl substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Hyroxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an R₁₇-bromide to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-R₁₇-oxyaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 19 discloses the conversion of a 3-thio substituent at the R₇ position in Formula I-CP (“Polycyclic 3-thiophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an R₁₇-bromide to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-R₁₇thiaaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”). “Polycyclic 3-R₁₇thiaaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols” can be oxidized to sulfonyl compounds of Formula I-CP (“Polycyclic 3-R₁₇sulfonylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 24 discloses the conversion of a 3-nitro substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Nitrophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by hydrogenation to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Aminophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”). “Polycyclic 3-Aminophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols” can be acylated to acyl amide compounds of Formula I-CP (“Polycyclic 3-R₁₇-C(O)amidophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Schemes 25 and 26 disclose the conversion of a 3-amino substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Aminophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with carbonyl compounds to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-(Saturated Nitrogen Heterocycl-lyl)aryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols” and (“Polycyclic 3-(Unsaturated Nitrogen Heterocycl-lyl)aryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”, respectively).

Scheme 27 discloses the conversion of a 3-methoxycarbonyl substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Carbomethoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with amination reagents to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Carboxamidophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 28 discloses the conversion of a 3-cyano substituent at the R₇ position in Formula I-CP (“Polycyclic 3-Cyanophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with organometallic reagents to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula 1-CP (“Polycyclic 3-Acylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”). Said “Polycyclic 3-Acylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”, according to Scheme 29 can be reduced to hydroxyl compounds of Formula I-CP (“Polycyclic 3-hydroxysubstitutedmethylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 36 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula I-CP (“Polycyclic 3-Carbomethoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with amination reagents to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP “Polycyclic 3-Carboxamdophenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 37 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula I-CP (“Polycyclic 3-Carbomethoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an organometallic reagent to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP “Polycyclic 3-(bis-R₂₀-hydroxymethyl)aryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 38 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula I-CP (“Polycyclic 3-Carbomethoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with lithium aluminum hydride to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-Hydroxymethylphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 39 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula I-CP (“Polycyclic 3-Carbomethoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction with an alkylation reagent to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3-(bis- R₂₁-hydroxymethyl)phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Scheme 55 discloses the conversion of a 3-methoxycarbonyl substituent at the R₁₀ position in Formula I-CP (“Polycyclic 3-Carbomethoxyphenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) compounds by reaction intially with an amidation reagent and then an R₂₀-organometallic reagent to afford, after isolation and purification as described above for Schemes 2,5,6,7, and 11, additional compounds of the present invention of Formula I-CP (“Polycyclic 3R₂₀-carbonyl)phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”).

Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. The hydroxyl group, wherein R₁₆ is a hydrogen and X is oxy, of compounds of Formulas I-H, I-HP, I-HPC, I-C, and I-CP can be readily convened to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters. Similarly, carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP are available from commerical sources or the references cited above, which are incorporated herein by reference.

Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. The hydroxyl group, wherein R₁₆ is a hydrogen and X is oxy, of compounds of Formulas 1-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents. In like manner, compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers. Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1,2, or 3 as shown in Scheme 3. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-H, I-HP, I-C, I-CP, I-HPC, Cyclo I-H, Cyclo I-C, and Cyclo I-CP are available from commerical sources or the references cited above, which are incorporated herein by reference.

Formula I-H (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-alkanols”), Formula I-HP (“Generic Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated I-Substitutedamino-2-propanols”), Formula I-HPC (“Polycyclic Aryl-Heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”), Formula I-C (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino+1)-Alkanols”), and Formula I-CP (“Polycyclic Phenyl (R)-Chiral Halogenated 1-Substitutedamino-2-Propanols”) and certain other compounds of this invention can be converted, according to Schemes 17 and 18, to the corresponding cyclic derivatives represented by “Tricyclic tertiary-oxyalkylamines” and exemplified by Formulas Cyclo I-H (“Polycyclic Aryl and Heteroaryl (R)-Chiral Halogenated (N+1)-Cycloazaalkoxy”), Cyclo I-C (“Polycyclic Aryl Phenyl (R)-Chiral Halogenated (N+1)-Cycloazaalkoxy”) and Cyclo I-CP (“Polycyclic Phenyl Phenyl (R)-Chiral Halogenated Cycloazaalkoxy”). The hydroxyl group, wherein R₁₆ is a hydrogen and X is oxy, of compounds of Formulas I-H, I-HP, I-C, I-CP, and I-HPC can be cyclized to corresponding cyclic ethers. Compounds suitable for cyclization will normally have at least one leaving group within 5 to 10 continuous atoms of the hydroxyl group wherein R₁₆ is a hydrogen and X is oxy. Most preferrably the leaving group will be within 5 to 7 atoms of the hydroxyl group so as to form a 6 to 8 membered ring heteroatom containing ring. When the leaving group is part of an aromatic ring system, the leaving group will be preferrably in an ortho position. Suitable leaving groups generally include halides, sulfates, sulfonates, trisubsituted amino, disubstituted sulfonium, diazonium, and like, and, in the case of aromatic systems, also includes nitro, alkoxy, aryloxy, heteroaryloxy, and alkylthio.

The cyclization reaction to form “Tricyclic tertiary-oxyalkylamines” of Formulas Cyclo I-H, Cyclo I-C and Cyclo I-CP can be accomplished by aromatic and aliphatic nucleophilic substitution reactions such as those disclosed in March's Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, especially at pages 293-412 and 649-658 and the references cited therein, which are incorporated herein by reference. Hydroxyl containing suitably substituted compounds can be converted to a cyclic analog by heating a suitably substituted compound under anhydrous conditions in a suitable solvent, such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetraglyme, or hexamethylphosphoramide, in the presence of a suitable base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium tertiary-butoxide, or lithium diisopropylamide. Alternately, sodium amide in anhydrous ammonia solvent can be used. Temperatures in the range of −20° C. to 200° C. can be used for time periods of 30 minutes to more than 24 hours. The preferred temperature can be selected by standard synthetic chemical technique balancing maximum yield, maximum purity, cost, ease of isolation and operation, and time required. Isolation of the “Tricyclic tertiary-oxyalkylamines” can be effected as described above for other tertiary-oxyalkylamines. Representative “Tricyclic tertiary-oxyalkylamines” prepared using the methodology described above are included in Table 8.

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

TABLE 8 Structure of Substituted Tricyclictertiary-2-oxyalkylamines.

Y Z R₅ K₁—R₆ R₁₀ K₂—R₁₁ R₁₂ R₁₃ CH₂ — 4-chloro-3- C—H H C—CF₃ H H ethylphenoxy CH₂ — 4-chloro-3- N H C—CF₃ H H ethylphenoxy CH₂ — 4-chloro-3- C—H H C—H CF₃ H ethylphenoxy CH₂ — 4-chloro-3- N H C—H CF₃ H ethylphenoxy CH₂ — 4-chloro-3- C—H H N CF₃ H ethylphenoxy — — 4-chloro-3- C—H H C—CF₃ H H ethylphenoxy — — 4-chloro-3- N H C—CF₃ H H ethylphenoxy — — 4-chloro-3- C—H H C—H CF₃ H ethylphenoxy — — 4-chloro-3- N H C—H CF₃ H ethylphenoxy — — 4-chloro-3- C—H H N CF₃ H ethylphenoxy

Y Z R₇ K₁—R₆ R₁₀ K₂—R₁₁ R₅ R₉ CH₂ — 4-chloro-3- C—H OCF₂CF₂H C—H H H ethylphenoxy CH₂ — 4-chloro-3- N OCF₂CF₂H C—H H H ethylphenoxy CH₂ — 4-chloro-3- C—H OCF₂CF₂H N H H ethylphenoxy CH₂ — phenoxy C—H OCF₂CF₂H C—H H H CH₂ — phenoxy N OCF₂CF₂H C—H H H CH₂ — phenoxy C—H OCF₂CF₂H N H H CH₂ — 4-chloro-3- C—H CF₂CF₃ C—H H H ethylphenoxy CH₂ — 4-chloro-3- N CF₂CF₃ C—H H H ethylphenoxy CH₂ — 4-chloro-3- C—H CF₂CF₃ N H H ethylphenoxy CH₂ — phenoxy C—H CF₂CF₃ C—H H H CH₂ — phenoxy N CF₂CF₃ C—H H H CH₂ — phenoxy C—H CF₂CF₃ N H H CH₂ — 4-chloro-3- C—H CF₃ C—H H H ethylphenoxy CH₂ — 4-chloro-3- N CF₃ C—H H H ethylphenoxy CH₂ — 4-chloro-3- C—H CF₃ N H H ethylphenoxy CH₂ — phenoxy C—H CF₃ C—H H H CH₂ — phenoxy N CF₃ C—H H H CH₂ — phenoxy C—H CF₃ N H H CH₂ — 4-chloro-3- C—H OCF₂CF₂H C—H H F ethylphenoxy CH₂ — 4-chloro-3- N OCF₂CF₂H C—H H F ethylphenoxy CH₂ — 4-chloro-3- C—H OCF₂CF₂H N H F ethylphenoxy CH₂ — 4-chloro-3- C—H 2-furyl C—H H H ethylphenoxy CH₂ — 4-chloro-3- N 2-furyl C—H H H ethylphenoxy CH₂ — 4-chloro-3- C—H 2-furyl N H H ethylphenoxy CH₂ — 4-chloro-3- C—H SCF₃ C—H H H ethylphenoxy CH₂ — 4-chloro-3- N SCF₃ C—H H H ethylphenoxy CH₂ — 4-chloro-3- C—H SCF₃ N H H ethylphenoxy

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the preceding schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by ¹H NMR and mass spectrometry. These compounds also may be formed in VIVO.

The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated.

EXAMPLE 1

(2R,S)-3-[(3-Phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol

EX-1A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetaachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h, then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO₄, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. ¹H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]⁺.

EX-1B) The crude product (56 g, 0.14 mol) from EX-1A in 200 mL of cyclohexane was added dropwise under nitrogen to a solution of 3-phenoxyaniline (89 g, 0.480 mol) in 500 mL of cyclohexane. The reaction mixture was refluxed overnight, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a dark oil. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 44.96 g (83%) of the desired N-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a yellow oil. ESMS m/z=392 [M+H]⁺.

To a mixture of the amine product (15.0 g, 0.038 mol) from EX-1B and 1,1,1-tri-fluoro-2,3-epoxypropane (8.58 g, 0.077 mol, TCI) was added a suspension of ytterbium (III) trifluoromethanesulfonate (2.37 g, 0.0031 mol) in 15 mL of acetonitrile. The resulting mixture was heated at 50° C. in a sealed glass vial for 1.5 h. The reaction mixture was cooled to room temperature then diluted with water and ethyl acetate and extracted. The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 12.03 g (62%) of the desired (2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil. Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd. 504.1410 [M+H]⁺, found: 504.1431. ¹H NMR (CDCl₃) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ −79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 2

(2R)-3-[(3-Phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

On a Chiralpak AD HPLC column, (2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (12.2 g, 0.024 mol) from EX-1 was purified by chiral chromatography to give 1.4 g (0.003 mol, 12%) of (2R)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol as a light yellow oil. Chiral purification was accomplished by eluting with 1:9 isopropanol in heptane at 1.0 mL/min with 250 nm UV detection. The product eluted at 8.43 min. [α]₅₈₉=+16.8.0 (c 0.125 g/dL, CH₃CN), [α]₃₆₅=+84.0 (c 0.125, CH₃CN). Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd.: 504.1410 [M+H]⁺, found: 504.1388. ¹H NMR (CDCl₃) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ −79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 3

(2S)-3-[(3-Phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

On a Chiralpak AD HPLC column, (2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (12.2 g, 0.024 mol) from EX-1 was purified by chiral chromatography to give 10.5 g (0.021 mol, 86%) of (2S)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol as a light yellow oil. Chiral purification was accomplished by eluting with 1:9 isopropanol in heptane at 1.0 mL/min with 250 nm UV detection. The product eluted at 6.36 min. [α]₅₈₉=−17.0 (c 0.265 g/dL, CH₃CN), [α]₃₆₅=−85.7 (c 0.265, CH₃CN). Anal. calcd. For C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd.: 504.1410 [M+H]⁺, found: 504.1431. ¹H NMR (CDCl₃) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ −79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

EXAMPLE 4

(2R)-3-[(3-Phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

Using a procedure adopted from H. C. Brown et al. (J. Org Chem. 60, 41-46, (1995)), R-(+)-1,1,1-trifluoro-2,3-epoxypropane was prepared beginning with the transfer of (+)-B-chlorodiisopinocampheylborane ((+)-DIP-Cl, 1.2 kg, 3.74 mol) to a 5 L three neck flask containing 5 L of ether under nitrogen. Anhydrous ether (5 L) was added, and the mixture was stirred until the solids dissolved and the temperature equilibrated to 0° C. Then 3-bromotrifluoroacetone (326 mL, 3.14 mol) was added, and the reaction was stirred for 72 h while maintaining the temperature between −4 and +5° C. The reaction was followed by ¹⁹F NMR by removing an aliquot (20 μL), quenching with anhydrous methanol (0.6 mL), and referencing to external D₂O. The reduction was 68% complete after 48 h. The ether was removed under vacuum (100 torr to 0.1 torr), leaving a pale, viscous oil. A 5 L 3-neck flask equipped with stirrer, dropping funnel, and short-path distillation head with chilled receiver was charged with 50% (w/w) aqueous NaOH and heated to 40° C. With external heat removed, the quenched reduction mixture was added dropwise to the aqueous NaOH, with the rate controlled to maintain the pot temperature below 65° C. The product epoxide formed immediately, distilling over with a head temperature of 32-42° C. A yellow-orange solid byproduct was broken up by stirring and some foaming was observed. When the distillation was complete, 145 g (43%) of the desired R-(+)-1,1,1-trifluoro-2,3-epoxy-propane product was obtained as a clear, colorless oil. ¹H NMR (C₆D₆) δ 2.50 (m, 1H, CF₃CH), 2.15 (dd, 1H, J=2.10, 5.01 Hz), 1.75 (m, 1H). ¹⁹F NMR (C₆D₆) δ −75.4 (d, J=4.7 Hz). Chiral GC/MS analysis was performed on the corresponding diethylamine adduct using a gamma cyclodextrin column (Supelco gammadex120 G-cyclodextrin fused silica): 4 drops of the epoxide, R-(+)-1,1,1-trifluoro-2,3-epoxypropane, and 4 drops of diethylamine were heated briefly in a sealed vial, cooled, diluted with methyl t-butyl ether, and analyzed. Found: two gc peaks: 10.97 min and 11.11 min (ratio 1:230; 99% ee), where the R-product predominated. MS calcd. for C₇H₁₄F₃NO: m/z=186 [M+H]⁺, found: 186, for both gc peaks. In contrast, the diethylamine adduct obtained with the TCl trifluoromethyl-oxirane (lot OGH01) from EX-1, gave 2 peaks with identical MS signals m/z=186, 10.96 min and 11.12 min (ratio 8.5:1; 79% ee), where the S-product predominated.

To a mixture N-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-amine from EX-1B (1.48 g, 0.0038 mol) and R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.64 g, 0.0057 mol) was added a suspension of ytterbium (III) trifluoro-methanesulfonate (0.23 g, 0.0004 mol) in 1.5 mL of acetonitrile. The resulting mixture was heated at 50° C. in a sealed glass tube for 1.5 h. The reaction mixture was cooled to room temperature then diluted with water and ethyl acetate and extracted. The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 1.2 g (63%) of the desired (2R)-3-[(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a pure yellow oil (>96% ee by chiral HPLC analysis), which was identical in all respects to EX-2. Anal. calcd. for C₂₄H₂₀F₇NO₃: C, 57.26; H, 4.00; N, 2.78. found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd.: 504.1410 [M+H]⁺, found: 504.1431. ¹H NMR (CDCl₃) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). ¹⁹F NMR (CDCl₃) δ −79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).

Additional examples can be prepared by one skilled in the art using similiar methods and commercially available epoxides. For example, 3-[(3-phenoxyphenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1-chloro-2-propanols can be prepared from the reaction of N-(3-phenoxyphenyl)-[[3-(trifluoromethoxy)phenyl]methyl]amine with either (R)-epichlorohydrin or (S)-epichlorohydrin, as illustrated in Example Table 1.

Example Table 1. 3-[(3-phenoxyphenyl)[[3- (trifluoromethoxy)phenyl]methyl]amino]-1-chloro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M + H]⁺ 5 OH H 452.1240 452.1245 6 H OH 452.1240 452.1259

EXAMPLE 7

(2R)-3-[(3,4,5-Trimethoxyphenyl)[[3-(trifuoromethylthio)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol

EX-45A) To a 1,2-dichloroethane (12 mL) solution of 3,4,5-triethoxyaniline (0.80 g, 4.4 mmol) was added (3-trifluoromethylthio)benzaldehyde (0.90 g, 4.4 mmol), NaB(OAc)₃H (1.20 g, 5.66 mmol) and acetic acid (0.26 mL, 4.5 mmol). The cloudy solution was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO₃ and brine, dried (MgSO₄) and evaporated to give 1.58 g (96%) of the desired N-(3,4,5-trimethoxyphenyl)[[3-trifluoromethylthiophenyl]methyl]amine product as an off-white solid. MS: m/z=373.8 [M+H]⁺.

To an acetonitrile (3.2 mL) solution of amine (1.20 g, 3.2 mmol) from EX-45A was added R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.55 mL, 6.4 mmol) from EX-4 and Yb(OTf)₃ (0.40 g, 0.64 mmol). The cloudy solution was stirred in a sealed flask at 50° C. for 18 h. The cooled reaction mixture was diluted with diethyl ether and washed with water and brine. The organic layer was dried (MgSO₄) and evaporated to an oil. Purification by flash column chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was triturated with hexanes to give a white solid. The precipitate was isolated by filtration and dried in vacuo to give 0.82 g (53%) of the desired (2R)-3-[(3,4,5-trimethoxyphenyl)[[3-(trifluoromethylthio)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol product as a white solid, m.p. 88.9-89.1° C. (95% ee by chiral HPLC). Anal. calcd. for C₂₀H₂₁NO₄SF₆: C, 49.48; H, 4.36; N, 2.89. Found: C, 49.29; H, 4.21; N, 2.8 1. HRMS calcd.: 486.1174 [M+H]⁺, found: 486.1158. ¹H NMR (C₆D₆) δ 3.10 (d, 1H), 3.18 (dd, 1H), 3.32 (s, 6H), 3.53 (d, 1H), 3.64 (s, 3H), 4.01 (m, 1H), 4.21 (dd, 2H), 5.70 (s, 2H), 6.80 (t, 1H), 6.94 (d, 1H), 7.23 (d, 1H), 7.37 (s, 1H). [α]₅₈₉=+26.8 (c 1.099 g/dL, CHCl₃).

EXAMPLE 8

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-8A) To a solution of 1,3-dinitrobenzene (16.8 g, 0.1 mol) and 4-chloro-3-ethylphenol (15.6 g, 0.1 mol) in 200 mL of dimethylsulfoxide was added cesium carbonate (65 g, 0.2 mol). The reaction mixture was heated at 100° C. under nitrogen overnight then cooled to room temperature. The reaction mixture was filtered through celite then rinsed with diethyl ether and a small amount of water. The filtrate was extracted several times with diethyl ether. The organic layers were combined, washed with water and brine, dried over MgSO₄, and concentrated in vacuo to give 21.8 g (78%) of the desired 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C₁₄H₁₂ClNO₃: 295.0849 [M+NH₄]⁺, found 295.0862.

EX-8B) To a solution of 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (10 g, 0.036 mol) from EX-A in 400 mL of glacial acetic acid and 1 mL of water was added zinc metal (20 g, 0.305 mol) at room temperature, and the resultant mixture was stirred for 1 h. The reaction mixture was filtered through celite. The filtrate was neutralized with ammonium hydroxide and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO₄, and concentrated in vacuo to give 10 g (100%) of the desired 3-(4-chloro-3-ethylphenoxy)aniline product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C₁₄H₁₄ClNO: 248.0842 [M+H]⁺, found: 248.0833.

EX-8C) To a solution of 3-(4-chloro-3-ethylphenoxy)aniline (2.0 g, 8.1 mmol) from EX-8B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.6 g, 7.3 mmol) in 30 mL of dichloroethane was added sodium triacetoxyborohydride (2.0 g, 9.7 mmol) and glacial acetic acid (0.51 mL, 8.9 mmol). The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO₄, and concentrated in vacuo to give 3.5 g (95%) of the desired N-[(4-chloro-3-ethylphenoxy)phenyl]-3-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₃H₂₀ClF₄NO₂: 454.1197 [M+H]⁺, found: 454.1220.

A solution of N-[(4-chloro-3-ethylphenoxy)phenyl]-3-[[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amine (1.8 g, 4.0 mmol) from EX-8C, R-(+)-1,1,1-trifluoro-2,3-epoxy-propane (0.64 g, 0.0057 mol) from EX-4, and ytterbium (III) trifluoromethanesulfonate (0.25 g, 0.4 mmol) in 1.5 mL of acetonitrile was heated at 40° C. in a sealed glass tube for 1 h. The reaction mixture was cooled to room temperature then diluted with water and diethyl ether and extracted. The ether layer was washed with water and brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to afford 1.5 g (66%) of the desired (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-tri-fluoro-2-propanol product as a yellow oil (96% ee by chiral HPLC analysis). [α]₅₈₉ ²⁵=+36.9 (c 1.044 g %, CHCl₃), [α]₃₆₅ ²⁵=+189.7 (c 1.044 g %, CHCl₃). The refractive index @ 25° C. is 1.5275. Anal. calcd. for C₂₆H₂₃ClF₇NO₃: C, 55.18; H, 4.10; N, 2.48. found: C, 54.92; H, 4.05; N, 2.33. HRMS calcd.: 566.1330 [M+H]⁺, found: 566.1323. ¹H NMR (CDCl₃) δ 7.30 (t, 1H), 7.20 (d, 1H), 7.15 (t, 1H), 7.08 (t, 2H), 7.00 (s, 1H), 6.86 (d, 1H), 6.68 (dd, 1H), 6.48 (dd, 1H), 6.36 (dd, 1H), 6.34 (t, 1H), 5.81 (tt, 1H), 4.62 (s, 2H), 4.32 (m, 1H), 3.84 (dd, 1H), 3.55 (dd, 1H), 2.67 (q, 2H), 2.45 (bs, 1H), 1.17 (t, 3H). ¹⁹F NMR (CDCl₃) δ 79.22 (d, 3F), −88.57 (m, 2F), −137.16 (dt, 2F).

Additional examples of (2R)-3-[[3-(substituted-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols and (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-substituted-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Tables 2 and 3, respectively.

Example Table 2. (2R)-3-[[3-(Substituted-phenoxy)phenyl][[3-(1,1,2,2- tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 9 4-methyl 518.1566 518.1587 10 3-isopropyl 546.1879 546.1900 11 3-ethyl 532.1723 532.1713

Example Table 3. (2R)-3-[[3-(4-Chloro-3-ethylphenoxy)phenyl][[3- substituted-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 12 3-trifluoromethoxy 534.1271 534.1309 13 3-trifluoromethyl, 4-fluoro 536.1228 536.1265 14 2-fluoro, 4-trifluoromethyl 536.1228 536.1241 15 2-trifluoromethyl, 4-fluoro 536.1228 536.1245 16 2-fluoro, 5-trifluoromethyl 536.1228 536.1252 17 2-fluoro, 6-trifluoromethyl 536.1228 536.1199

EXAMPLE 18

(2R)-3-[[3-(4-Chloro-3-ethylphenoxy)phenyl][[3-(1,1,1,2,2-pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-18A) Sodium pentafluoroethyl propionate (8.4 g, 50 mmol) and 3-iodotoluene (5.5 g, 25 mmol) were dissolved in anhydrous DMF (300 mL) under nitrogen. CuI (9.5 g, 50 mmol) was added, and the mixture was heated to 160° C. under nitrogen for 4 h, at which time a 15 mL fraction of a mixture of DMF and 3-pentafluoroethyl toluene was collected. The distillate was diluted with Et₂O and was washed with brine. The ether layer was dried over MgSO₄, filtered and concentrated in vacuo to give 5.25 g (55%) of the desired 3-pentafluoroethyl-toluene product as a colorless oil. ¹H NMR (CDCl₃) δ 7.36 (m, 4H), 2.40 (s, 3H). ¹⁹F NMR (CDCl₃) δ −85.2 (s, 3F), −115.2 (s, 2F).

EX-18B) The 3-pentafluoroethyl-toluene (2.9 g, 13.8 mmol) product from EX-18A and N-bromosuccinimide (2.5 g, 13.8 mmol) were dissolved in CCl₄ (25 mL). AIBN (50 mg, 0.3 mmol) was added, and the mixture was refluxed for 3.5 h under N₂. The reaction mixture was cooled to room temperature and diluted with water. The layers were separated, and the organic layer was washed with brine, dried with anhydrous MgSO₄, filtered, and concentrated in vacuo to give 3.4 g (87%) of a colorless oil. The ¹H NMR spectrum indicated that the crude product contained 3-pentafluoroethyl-benzylbromide (70%), the benzyldibromide (10%) and pentafluoroethyl toluene (20%). ¹H NMR (CDCl₃) δ 7.60 (m, 2H), 7.50 (m, 2H), 4.50 (s, 2H). ¹⁹F NMR (CDCl₃) δ −−85.1 (s, 3F), −115.4 (s, 2F).

EX-18C) A solution of 3-(4-chloro-3-ethylphenoxy)aniline (1.7 g, 6.9 mmol) was prepared in cyclohexane (13 mL). A solution of crude 3-pentafluoroethyl 10 benzylbromide (1 g, 3.5 mmol) product from EX-18B in cyclohexane (10 mL) was added dropwise under nitrogen over 3 min. The reaction mixture was refluxed under N₂ for 24 h and then was cooled to room temperature. The mixture was diluted with Et₂O and saturated aqueous NaHCO₃. The layers were separated, and the aqueous layer was extracted with Et₂O. The organic layer was washed with brine, dried with anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexanes in ethyl acetate (95:5) which gave 0.56 g (35%) of the desired N-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoro-ethyl)phenyl]-methyl]amine product as a brown oil. ¹H NMR (CDCl₃) δ 7.53 (m, 4H), 7.27 (d, 1H), 7.15 (t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt, 2H), 6.30 (t, 1H), 4.41 (s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). ¹³C NMR (CDCl₃) δ 158.6, 156.1, 143.4, 141.3, 140.2, 131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8, 108.8. 103.9, 48.5, 27.5, 14.1. ¹⁹F NMR (CDCl₃) δ −85.1 (s, 3F), −115.2 (s, 2F). HRMS calcd. for C₂₃H₁₉ClF₅NO: 456.1154 [M+H]⁺, found: 456.1164.

The N-[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amine (0.4 g, 0.88 mmol) product of EX-18C was dissolved in anhydrous acetonitrile (1.5 mL). R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.22 g, 1.94 mmol) and Yb(OTf)₃ (22 mg, 0.035 mmol) were added, and the reaction mixture was stirred under N₂ at 45° C. in a sealed glass tube for 15 h. The reaction mixture was then cooled to room temperature and diluted with Et₂O and saturated aqueous NaHCO₃. The layers were separated and the aqueous layer was extracted with Et₂O. The ether layers were combined, washed with brine, dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The viscous oil was adsorbed onto silica gel and purified by column chromatography eluting with hexanes in ethyl acetate (95:5) which gave 0.32 g (64%) of the desired (2R)-3-[(4-chloro-3-ethylphenoxy)phenyl[[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a viscous, colorless oil. ¹H NMR (CDCl₃) δ 7.47 (m, 4H), 7.23 (m, 3H), 6.90 (d, 1H), 6.72 (dd, 1H), 6.52 (d, 1H), 6.42 (m, 2H), 4.73 (s, 2H), 4.39 (m, 1H), 3.91 (dd, 1H), 3.58 (m, 2H), 2.73 (q, 2H), 2.57 (s, 1H), 1.22 (t, 3H). ¹⁹F NMR (CDCl₃) δ −79.2 (s, 3F),−84.9 (s, 3F), −115.2 (s, 2F). HRMS calcd. for C26H₂₂ClF₈NO₂: 568.1290 [M+H]⁺, found: 568.1296.

EXAMPLE 19

(2R)-3-[[3-(3-Trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-19A) To a solution of 1,3-dinitrobenzene (4.5 g, 0.03 mol) and 3-trifluoromethoxy-phenol (4.8 g, 0.03 mol) in 54 mL of dimethylsulfoxide was added cesium carbonate (21.8 g, 0.07 mol). The reaction mixture was heated at 100° C. under nitrogen overnight then cooled to room temperature. The reaction mixture was diluted with water and extracted with diethyl ether several times. The organic layers were combined, washed with 1 N HCl and water, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 3.0 g (38%) of the desired 3-(3-trifluoro-methoxyphenoxy)nitrobenzene product as a yellow-orange liquid which was 85% pure by reverse phase HPLC analysis. This material was carried on without further purification.

EX-19B) To a solution of 3-(3-trifluoromethoxyphenoxy)nitrobenzene (3.0 g, 0.01 mol) from EX-19A in 100 mL of glacial acetic acid was added zinc metal (6.6 g, 0.1 mol) at room temperature, and the resultant mixture was stirred for 1 h. The reaction mixture was filtered through celite. The filtrate was neutralized with ammonium hydroxide and extracted with diethyl ether then ethyl acetate. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 1.2 g (44%) of the desired 3-(3-trifluoromethoxyphenoxy)aniline product as a yellow oil which was 98% pure by reverse phase HPLC analysis. Anal. calcd. for C₁₃H₁₀F₃NO₂: C, 58.00; H, 3.74; N, 5.20. found: C, 57.68; H, 3.57; N, 5.14. HRMS calcd.: 270.0742 [M+H]⁺, found: 270.0767.

EX-19C) To a solution of 3-(3-trifluoromethoxyphenoxy)aniline (1.0 g, 3.7 mmol) from EX-19B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.83 g, 3.7 mmol) in 18.5 mL of dichloroethane was added sodium triacetoxyborohydride (1.0 g, 4.7 mmol) and glacial acetic acid (0.25 mL, 4.3 mmol). The reaction mixture was stirred at room temperature overnight then quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried over MgSO₄ and concentrated in vacuo to give 1.8 g (100%) of the desired [3-(3-trifluoromethoxy-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl] amine product as a yellow oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C₂₂H₁₆F₇NO₃: 476.1097 [M+H]⁺, found: 476.1069. This material was carried on to the next step without further purification.

A solution of [3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amine (1.8 g, 3.7 mmol) from EX-19C, R-(+)-1,1,1-trifluoro-2,3-epoxy-propane (0.57 g, 5.2 mmol), and ytterbium (III) trifluoromethanesulfonate (0.24 g, 0.38 mmol) in 2.0 mL of acetonitrile was heated at 40° C. in a sealed glass tube overnight. At this time reverse phase HPLC analysis indicated that the reaction was only 50% complete. Additional ytterbium (III) trifluoromethanesulfonate and R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.26 g, 2.3 mmol) were added to the reaction mixture and again heated at 40° C. in a sealed gass tube for 48 h. The reaction mixture was cooled to room temperature then diluted with water and methylene chloride and extracted. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by reverse phase HPLC eluting with 30% to 90% acetonitrile in water to afford 1.25 g (23%) of the desired (2R)-3-[[3-(3-trifluoromethoxyphenoxy) phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as yellow-brown oil (90% ee by chiral HPLC analysis). HRMS calcd. for C₂₅H₁₉F₁₀NO₄: 588.1233 [M+H]⁺, found: 588.1225. ¹H NMR (CDCl₃) δ 7.35-7.18 (m, 3H), 7.12 (t, 2H), 7.01 (s, 1H), 6.93 (d, 1H), 6.85 (d, 1H), 6.82 (s, 1H), 6.56 (dd, 1H), 6.47 (dd, 1H), 6.41 (s, 1H), 5.88 (t, 1H), 4.66 (s, 2H), 4.35 (m, 1H), 3.86 (d, 1H), 3.59 (dd, 1H), 2.02 (s, 1H). ¹⁹F NMR (CDCl₃) δ -58.31 (s, 3F), -79.24 (d, 3F), -88.57 (m, 2F), -137.16 (dt, 2F).

EXAMPLE 20

(2R)-3-[[[3-(1,1 2,2-Tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol

EX-20A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred at room temperature for 6 h then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO₄, and concentrated in vacuo to give 11.82 g (83%) of the desired 3-[[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. ¹H NMR (acetone-d₆) δ 7.01-7.38 (m, 5H), 6.26-6.44 (m, 3H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.34 (s, 2H).

EX-20B) A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (5.1 g, 16.2 mmol) from EX-20A, R-(+)-1,1,1-trifluoro-2,3-epoxypropane (1.5 mL, 17.4 mmol), and ytterbium trifluoromethanesulfonate (1.0 g, 10 mol%) in 10 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 4 h. The reaction mixture was cooled to room temperature, then diluted with water and diethyl ether and extracted. The ether layer was washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO₄, and concentrated in vacuo to give 5.64 g (81%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxy-propyl)amino]-phenol product as a yellow oil. ¹H NMR (acetone-d₆) δ 7.41 (t, 1H), 7.23 (d, 1H), 7.16-7.20 (m, 2H), 6.97 (t, 1H), 6.42 (tt, 1H), 6.18-6.24 (m, 3H), 4.77 (s, 2H), 4.434.48 (m, 1H), 3.58 (dd, 1H), 3.39 (dd, 1H).

To a solution of (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy]phenyl]methyl][3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol) from EX-20B and 3-trifluoromethylbenzyl bromide (70.0 mg, 0.27 mmol) in 2.5 mL of acetone was added cesium carbonate (100 mg, 0.31 mmol). The reaction mixture was heated at 60° C. for 18 h then cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 63.3 mg (45%) of the desired (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C₂₆H₂₁F₁₀NO₃: 586.1440 [M+H]⁺, found: 586.1419. ¹H NMR (acetone-d₆) δ 7.61-7.82 (m, 4H), 7.41 (t, 1H), 7.25 (d, 1H), 7.10-7.21 (m, 3H), 6.34-6.67 (m, 4H), 5.73 (d, 1H), 5.19 (s, 2H), 4.82 (s, 2H), 4.34-4.48 (m, 1H), 3.99 (dd, 1H), 3.68 (dd, 1H).

Additional examples of (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]-[3-[[aryl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in. Example Table 4.

Example Table 4. (2R)-3-[[[3-(1,1,2,2-tetrafluoro- ethoxy)phenyl]methyl][3-[[aryl]methoxy]phenyl]amino]- 1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 21 3,5-difluorobenzyl 554.1378 554.1352 22 3-trifluoromethoxybenzyl 602.1389 602.1390 23 3-isopropyl 470.1566 464.1601

EXAMPLE 24

(2R)-3-[[3-[[3-(Trifluoromethoxy)phenyl]methoxy]phenyl][[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

(2R)-3-[[3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol can be prepared by one skilled in the art using similar methods starting from 3-(trifluoromethoxy)-benzaldehyde. HRMS calcd. for C₂₅H₂₀F₉NO₄: 570.1327 [M+H]⁺, found: 570.1325. ¹H NMR (acetone-d₆) δ 7.43 (t, 1H), 7.32 (d, 1H), 7.18-7.23 (m, 2H), 7.01-7.16 (m, 3H), 6.92-7.00 (m, 1H), 6.38-6.45 (m, 3H), 5.12 (s, 2H), 4.81 (s, 2H), 4.41-4.53 (m, 1H), 3.98 (dd, 1H), 3.63 (dd, 1H).

Additional examples of (2R)-3-[[3-[[aryl]methoxy]phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 5.

Example Table 5. (2R)-3-[[3-[[aryl]methoxy]phenyl][[3- (trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 25 4-trifluoromethoxybenzyl 570.1327 570.1299 26 3,5- 622.1252 622.1252 di(trifluoromethyl)benzyl 27 3-trifluoromethylbenzyl 554.1378 554.1369 28 3,5-difluorobenzyl 522.1315 522.1259 29 benzyl 486.1504 486.1504 30 isopropyl 438.1504 438.1509 31 cyclohexylmethyl 492.1973 492.1973 32 cyclopentyl 464.1660 464.1641

EXAMPLE 33

(2R)-3-[[3-(4-Fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)-phenyl]methyl]amino-1,1,1-trifluoro-2-propanol

EX-33A) To a solution of 3-bromoaniline (5.7 mL, 52.6 mmol) and 3-trifluoro-methoxybenzaldehyde (10.0 g, 52.6 mmol) in 135 mL of dichloroethane was added sodium triacetoxyborohydride (14.5 g, 68.4 mmol) and glacial acetic acid (3.1 mL, 54.7 mmol). The reaction was stirred at room temperature for 2 h, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO₄, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to give 14.3 g (78%) of the desired of N-(3-bromophenyl)[[3-(trifluoromethoxy) phenyl]methyl]amine product as a dark brown oil. HRMS calcd. for C₁₄H₁₁BrF₃NO: 346.0055 [M+H]⁺, found: 346.0052.

EX-33B) A solution of of N-(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]-amine (10.0 g, 28.9 mmol) from EX-33A, R-(+)-1,1,1-trifluoro-2,3-epoxypropane (4.2 g, 37.6 mmol), and ytterbium (III) trifluoromethanesulfonate (1.79 g, 2.89 mmol) in 27 mL of acetonitrile was heated at 50° C. in a sealed glass tube overnight. The reaction mixture was cooled to room temperature and filtered through celite. The crude product was purified by column chromatography on silica gel eluting with 2:3 dichloromethane in hexane to afford 11.9 g (90%) of the desired (2R)-3-[[(3-bromophenyl)][[3-(tri-fluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil (98% ee by chiral HPLC analysis). HRMS calcd. for C₁₇H₁₄BrF₆NO₂: 458.0190 [M+H]⁺, found: 458.0197.

A suspension of 4-fluoro-3-methylphenol (98.0 μL, 0.88 mmol) and cesium carbonate (319.5 mg, 0.98 mmol) in 1 mL of N,N-dimethylacetamide was preheated at 60° C. for 5 minutes. To this solution was added 4 mL of a stock solution containing (2R)-3-[[(3-bromophenyl)][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.437 mmol) from EX-33B, 1-naphthoic acid (164 mg, 0.95 mmol), copper(I) trifluoromethansulfonate benzene complex (21.8 mg, 0.0434 mmol), 4 Å sieves (105 mg), and 4 mL of toluene. The reaction mixture was stirred at 105° C. for 3 weeks and 2 days. During that time, additional cesium carbonate and catalyst were added (a spatula tip of each) to the reaction three different times. The reaction was cooled to room temperature, filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 35% to 90% acetonitrile in water to afford 50.5 mg (23%) of the desired (2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C₂₄H₂₀F₇NO₃: 504.1410 [M+H]⁺, found: 504.1389. ¹H NMR (acetone-d₆) δ 7.44 (t, 1H), 7.24 (d, 1H), 7.08-7.21 (m, 3H), 6.98 (t, 1H), 6.75-6.85 (m, 1H), 6.68-6.74 (m, 1H), 6.53 (d, 1H), 6.21-6.34 (m, 2H), 4.79 (t, 2H), 4.46-4.53 (m, 1H), 3.95 (dd, 1H), 2.61-2.72 (m, 1H), 2.20 (s, 3H).

Additional examples (2R)-3-[[(aryloxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols can be prepared by one skilled in the art using similar methods, as shown in Example Table 6.

Example Table 6. (2R)-3-[[(aryloxy)phenyl][[3-(trifluoro- methoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 34 3-trifluoromethoxy 556.1170 556.1180 35 3-isopropyl 514.1817 514.1823 36 3,4-dimethyl 500.1660 500.1654 37 4-chloro-3-methyl 520.1114 520.1129 38 3-tert-butyl 528.1973 528.1942 39 3,4-dichloro 540.0568 540.0567 40 3,4-(CH₂CH₂CH₂CH₂)— 526.1817 526.1788

EXAMPLE 41

(2R)-3-[[3-(4-Methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-41A) To a solution of p-cresol (5.76 g, 0.053 mol) and 1,3-dinitrobenzene. (8.97 g, 0.053 mol) in 100 mL of dimethylsulfoxide was added cesium carbonate (43.4 g, 0.133 mol). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature, quenched with water, and extracted with diethyl ether. The organic layers were combined, washed with 0.1 N HCl and water, dried over MgSO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 8.0 g (66%) of the desired 3-(4-methylphenoxy)nitrobenzene product as a yellow oil. ¹H NMR (CDCl₃) δ 7.83 (s, 1H), 7.64 (t, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8 (d, 2H), 2.20 (s, 1H).

EX-41B) A solution of 3-(4-methylphenoxy)nitrobenzene (8.0 g, 0.035 mol) from EX-41A in 25 mL of ethanol under nitrogen was charged with 10% palladium on carbon (0.80 g). The resulting mixture was hydrogenated for 4 h at room temperature and 45 psi. The reaction mixture was filtered through celite and concentrated in vacuo to give 6.7 g (96%) of the desired 3-(4-methylphenoxy)aniline product as a yellow oil. ESMS m/z=200 [M+H]⁺ confirmed the desired C₁₃H₁₃NO product and the complete consumption of starting material.

EX-41C) To a solution of 3-(4-methylphenoxy)aniline (2.91 g, 0.015 mol) from EX-41B, and 3-(trifluoromethoxy)benzyaldehyde (3.24 g, 0.015 mol) in 50 mL dichioroethane was added sodium triacetoxyborohydride (4.02 g, 0.019 mol) and glacial acetic acid (0.99 g, 0.017 mol). The reaction mixture was stirred at room temperature for 18 h, then quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layers were combined, dried over MgSO₄ and concentrated in vacuo to give 5.38 g (91%) of the desired N-[3-(4-methylphenoxy)-phenyl)]-[[3-(trifluoromethoxy)phenyl]methyl]amine product as an orange oil. ESMS m/z=374 [M+H]⁺ confirmed the desired C₂₁H₁₈NO₂F₃ product and the complete consumption of starting material.

To a mixture of N-[3-(4-methylphenoxy)phenyl)]-[[3-(trifluoromethoxy)-phenyl]-methyl]amine(1.3 g, 0.0035 mol) from E-X41C and R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.59 g, 0.0053 mol) was added a suspension of ytterbium (III) trifluoromethanesulfonate (0.22 g, 0.0004 mol) in 1.3 mL of acetonitrile. The resulting mixture was heated at 50° C. in a sealed glass tube for 18 h. The reaction mixture was cooled to room temperature, then diluted with water and extracted with ethyl acetate. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 1.03 g (61%) of the desired (2R)-3-[3-(4-methyl-phenoxy)phenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propa-nol product as a pure yellow oil. Anal. calcd. for C₂₄H₂₁F₆NO₃: C, 59.38; H, 4.36; N, 2.89. Found: C, 59.17; H, 4.62; N, 2.80. HRMS calcd.: 486.1504 [M+H]^(+, found:) 486.,1513. ¹H NMR (C₆D₆) 8 6.82 (m, 8R), 6.60 (dd, 1H), 6.42 (dd, 1H), 6.3 8 (s, 1H),. 6.18 (dd, 1H), 4.00 (s, 2H), 3.63 (m, 1H), 3.40 (d, 1H), 3.02 (m, 1H), 2.00 (s, 3H), 1.40 (d, 1H). ¹⁹F NMR (C₆D₆) δ −57.98 (s, 3F), −78.50 (s, 3F).

Additional examples of (2R)-3-[3(substituted-phenoxy)phenyl]-[[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols can prepared by one skilled in the art using similar methods, as shown in Example Table 7.

Example Table 7. (2R)-3-[3-(substituted-phenoxy)phenyl][[3- (trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanols.

Calculated Observed Ex. Mass Mass No. R_(SUB) [M + H]⁺ [M + H]⁺ 42 4-fluoro 490.1253 490.1238

EXAMPLE 43

(2R)-3-[[3-(2-Bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-43A) To a solution of 3-aminophenol (5 g, 46 mmol), 1-bromo-2,4-difluoro-benzene (10 g, 50 mmol) and Cs₂CO₃ (16 g, 50 mmol) in 25 mL of dimethyl-fommamide was added solid (CuOTf)₂C₆H₆ (100 mg), and the mixture was stirred under nitrogen at 85° C. for 22 h, at which time HPLC analysis indicated that the reaction had gone to completion and formed two products. The DMF was removed under reduced pressure. The residue was diluted with ether and filtered through a celite pad. The pad was washed with ether and a small amount of water. The mixture was extracted with ether several times. The combined ether layers were washed with water and brine, then dried over MgSO₄. The dried organic layer was evaporated to give 10.2 g (80%) of the desired product, which consisted of a 11:1 ratio of 3-(2-bromo-5-fluoro-phenoxy)aniline and 3-(4-bromo-3-fluorophenoxy)aniline. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 8.8 g (68%) of the desired product as a yellow oil, which was a 25:1 ratio of 3-(2-bromo-5-fluorophenoxy)aniline and 3-(4-bromo-3-fluorophenoxy)aniline. HRMS calcd. for C₁₂H₉NOFBr: 281.9930 [M+H]⁺, found: 281.9950.

EX-43B) The 3-(2-bromo-5-fluorophenoxy)aniline (1.39 g, 4.95 mmol) product from EX-43A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.0 g, 4.5 mmol) were dissolved in 15 mL of dichloroethane and acetic acid (0.30 mL, 5.4 mmol), then solid NaBH(OAc)₃ (1.26 g, 5.9 mmol) was added. The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄, and evaporated to give 2.1 g (97%) of crude product, which was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 2.0 g (91%) of the desired 3-[3-(2-bromo-5-fluoro-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amine product, as a light yellow oil, >90% pure by HPLC analysis. HRMS calcd. for C₂₁H₁₅NO₂BrF₅: 488.0285 [M+H]⁺, found: 488.0269.

The 3-[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-methyl]amine (0.5 g, 2.0 mmol) product from EX-43B and R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.17 g, 2.0 mmol) from EX-4 were dissolved in 0.5 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.06 g, 0.1 mmol) was added, and the stirred solution was warmed to 40° C. for 1 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO₄. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 of ethyl acetate:hexane:ammonium hydroxide to give 0.4 g (67%) of the desired R-(+)-3-[[3-(2-bromo-5-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil (>84% ee by chiral HPLC analysis). Anal. calcd. for C₂₄H₁₈BrF₈NO₃: C, 48.02; H, 3.02; N, 2.33. found: C, 48.07; H, 3.14; N, 2.31. HRMS calcd.: 600.0420 [M+H]⁺, found: 600.0386. ¹H NMR (CDCl₃) δ 7.5 0 (dd, 1H), 7.30 (t, 1H), 7.18 (t, 1H), 7.07 (t, 2H), 6.99 (s, 1H), 6.70 (dt, 1H), 6.56 (dd, 1H), 6.52 (dd, 1H), 6.38 (dd, 1H), 6.32 (m, 1H), 5.87 (tt, 1H,), 4.65 (d, 2H), 4.33 (m, 1H), 3.85 (dd, 1H), 3.56 (dd, 1H), 2.48 (bs, 1H). NOE difference spectra confirmed that the isolated material was the indicated N-[3-(2-bromo-5-fluoro-phenoxy)phenyl]-3-aminopropanol product. ¹⁹F NMR (CDCl₃) δ 79.24 (d, 3F), −88.57 (m, 2F), −112.04 (q, 1H), −137.16 (dt, 2F).

EXAMPLE 44

2R)-N-2-Chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

EX-44A) 3-Trifluoromethoxybenzenemethanamine (1.15 g, 6 mmol) and R-(+)-1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined and stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0.67 g (37%) of pure (2R)-3-[[[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro2-propanol. ¹H NMR (CDCl₃) δ 7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H), 3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). ¹⁹F NMR (CDCl₃) δ −58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C₁₁H₁₁F₆NO₂: 304.0772 [M+H]⁺, found: 304.0794.

EX-44B) To a solution of p-fluorophenol 1.00 g (8.92 mmol) in 30 mL of tetrahydrofuran at 0° C. was added a 60% dispersion of sodium hydride in mineral oil (0.36 g, 8.92 mmol). After 30 min, cyanuric chloride (1.64 g, 8.92 mmol) was added as a heterogeneous mixture in tetrahydrofuran at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the mixture was cooled to 0° C., and a saturated aqueous NH₄Cl solution was added. The aqueous solution was extracted with diethyl ether (3×50 mL). The combined ether extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo to afford 1.34 g (58%) of the desired 2,4-dichloro-6-(4-fluorophenoxy)-1,3,5-triazine product as an off white solid which was taken on to the next step without purification. MS m/z=260 [M+H]⁺.

To a stirred solution of aminopropanol from EX44A (0.100 g, 0.330 mmol) in N,N-dimethylformamide at 0° C. was added the 2,4-dichloro-(4-fluorophenoxy)-1,3,5-triazine ether product from EX-44B (0.086 g, 0.330 mmol) as a solution in N,N-di-methylformnamide. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the reaction mixture was cooled to 0° C., and a saturated aq. NaHCO₃ solution was added. After stirring the reaction mixture for 30 min at room temperature, the aqueous layer was extracted with ether (3×30 mL). The combined ether extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo to give a yellow oil. The crude residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexanes to give 0.075 g (43%) of the desired (2R)-N-[2-chloro-6-(p-fluorophenoxy)-1,3,5-triazin-4-yl]-3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a pale yellow oil. HRMS calcd. for C₂₀H₁₄ClF₇N₄O₃: 526.0643 [M⁺], found: 526.0632. ¹H NMR (C₆D₆) δ 6.95 (s, 1H), 6.63 (m, 14H), 4.74 (d, 1H), 4.37 (d, 1H), 4.16 (d, 1H), 4.00 (d, 2H), 3.73 (m, 1H), 3.48 (m, 2H), 3.26 (m, 2H), 3.12 (m, 2H).

Based on the preceding procedures, additional substituted (2R)-3-[(N-aryl)-[[aryl]methyl]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, has shown in Example Table 8. Substituted (3R)-4-[N-(aryl)-[(aryl)methyl]amino]-1,1,1 2,2-pentafluoro-3-butanols are prepared by one skilled in the art using similar methods, as shown in Example Table 9. Substituted (2R)-3-[N-(aryl)[(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 10. Substituted (2R)-3-[N-(aryl)-[(aryl)methyl]amino]-1,1-difluoro-1-chloro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 11. Substituted (2R)-3-[N,N′-(diaryl)amino]-1,1,1-trifluoro-2-propanols are prepared by one skilled in the art using similar methods, as shown in Example Table 12.

Example Table 8. Substituted (2R)-3-[N-(aryl)-[(aryl)methyl]amino]- 1,1,1-trifluoro-2-propanols.

Ex. Ex. No. R_(SUB1) No. R_(SUB2)  45 3-isopropyl  69 3-CF₃O-benzyloxy  46 2-Cl, 3-Cl  70 3-CF₃-benzyloxy  47 3-CF₃O  71 3-F, 5-F-benzyloxy  48 4-F  72 cyclohexylmethyleneoxy  49 4-CH₃  73 benzyloxy  50 2-F, 5-Br  74 3-CF₃, 5-CF₃-benzyloxy  51 3-CF₃CF₂  75 4-CF₃O-benzyloxy  52 3-CH₃CH₂  76 4-CH₃CH₂-benzyloxy  53 3-CH₃, 5-CH₃  77 isopropoxy  54 3-(CH₃)₃C  78 3-CF₃-benzyl  55 4-F, 3-CH₃  79 isopropylthio  56 3-Cl, 4-Cl  80 cyclopentoxy  57 3,4-(CH₂)₄  81 3-Cl-5-pyridinyloxy  58 3-HCF₂CF₂O  82 3-CF₃S-benzyloxy  59 3-CHF₂O  83 3-CH₃, 4-CH₃-benzyloxy  60 3-(CH₃)₂N  84 2-F, 3-CF₃-benzyloxy  61 3-cyclopropyl  85 3-F, 5-CF₃-benzyloxy  62 3-(2-furyl)  86 4-(CH₃)₂CH-benzyloxy  63 3-CF₃CF₂  87 1-phenylethoxy  64 4-NH₂  88 4-F, 3-CH₃-benzoyl  65 3-CH₃, 4-CH₃, 5-CH₃  89 3-CF₃-phenyl  66 4-CH₃CH₂CH₂O  90 4-CH₃O-phenylamino  67 3-CF₃  91 cyclopropoxy  68 2-NO₂  92 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2)  93 3-isopropyl 117 3-CF₃O-benzyloxy  94 2-Cl, 3-Cl 118 3-CF₃-benzyloxy  95 3-CF₃O 119 3-F, 5-F-benzyloxy  96 4-F 120 cyclohexylmethyleneoxy  97 4-CH₃ 121 benzyloxy  98 2-F, 5-Br 122 3-CF₃, 5-CF₃-benzyloxy  99 4-Cl, 3-CH₃CH₂ 123 4-CF₃O-benzyloxy 100 3-CH₃CH₂ 124 4-CH₃CH₂-benzyloxy 101 3-CH₃, 5-CH₃ 125 isopropoxy 102 3-(CH₃)₃C 126 3-CF₃-benzyl 103 4-F, 3-CH₃ 127 isopropylthio 104 3-Cl, 4-Cl 128 cyclopentoxy 105 3,4-(CH₂)₄ 129 3-Cl-5-pyridinyloxy 106 3-HCF₂CF₂O 130 3-CF₃S-benzyloxy 107 3-CHF₂O 131 3-CH₃, 4-CH₃-benzyloxy 108 3-(CH₃)₂N 132 2-F, 3-CF₃-benzylOXy 109 3-cyclopropyl 133 3-F, 5-CF₃-benzyloxy 110 3-(2-furyl) 134 4-(CH₃)₂CH-benzyloxy 111 3-CF₃CF₂ 135 1-phenylethoxy 112 4-NH₂ 136 4-F, 3-CH₃-benzoyl 113 3-CH₃, 4-CH₃, 5-CH₃ 137 3-CF₃-phenyl 114 4-CH₃CH₂CH₂O 138 4-CH₃O-phenylamino 115 3-CF₃ 139 cyclopropoxy 116 2-NO₂ 140 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 141 3-isopropyl 165 3-CF₃O-benzyloxy 142 2-Cl, 3-Cl 166 3-CF₃-benzyloxy 143 3-CF₃O 167 3-F, 5-F-benzyloxy 144 4-F 168 cyclohexylmethyleneoxy 145 4-CH₃ 169 benzyloxy 146 2-F, 5-Br 170 3-CF₃, 5-CF₃-benzyloxy 147 4-Cl, 3-CH₃CH₂ 171 4-CF₃O-benzyloxy 148 3-CH₃CH₂ 172 4-CH₃CH₂-benzyloxy 149 3-CH₃, 5-CH₃ 173 isopropoxy 150 3-(CH₃)₃C 174 3-CF₃-benzyl 151 4-F, 3-CH₃ 175 isopropylthio 152 3-Cl, 4-Cl 176 cyclopentoxy 153 3,4-(CH₂)₄ 177 3-Cl-5-pyridinyloxy 154 3-HCF₂CF₂O 178 3-CF₃S-benzyloxy 155 3-CHF₂O 179 3-CH₃, 4-CH₃-benzyloxy 156 3-(CH₃)₂N 180 2-F, 3-CF₃-benzyloxy 157 3-cyclopropyl 181 3-F, 5-CF₃-benzyloxy 158 3-(2-furyl) 182 4-(CH₃)₂CH-benzyloxy 159 3-CF₃CF₂ 183 1-phenylethoxy 160 4-NH₂ 184 4-F, 3-CH₃-benzoyl 161 3-CH₃, 4-CH₃, 5-CH₃ 185 3-CF₃-phenyl 162 4-CH₃CH₂CH₂O 186 4-CH₃O-phenylamino 163 3-CF₃ 187 cyclopropoxy 164 2-NO₂ 188 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 189 3-isopropyl 213 3-CF₃O-benzyloxy 190 2-Cl, 3-Cl 214 3-CF₃-benzyloxy 191 3-CF₃O 215 3-F, 5-F-benzyloxy 192 4-F 216 cyclohexylmethyleneoxy 193 4-CH₃ 217 benzyloxy 194 2-F, 5-Br 218 3-CF₃, 5-CF₃-benzyloxy 195 4-Cl, 3-CH₃ 219 4-CF₃O-benzyloxy 196 3-CH₃CH₂ 220 4-CH₃CH₂-benzyloxy 197 3-CH₃, 5-CH₃ 221 isopropoxy 198 3-(CH₃)₃C 222 3-CF₃-benzyl 199 4-F, 3-CH₃ 223 isopropylthio 200 3-Cl, 4-Cl 224 cyclopentoxy 201 3,4-(CH₂)₄ 225 3-Cl-5-pyridinyloxy 202 3-HCF₂CF₂O 226 3-CF₃S-benzyloxy 203 3-CHF₂O 227 3-CH₃, 4-CH₃-benzyloxy 204 3-(CH₃)₂N 228 2-F, 3-CF₃-benzyloxy 205 3-cyclopropyl 229 3-F, 5-CF₃-benzyloxy 206 3-(2-furyl) 230 4-(CH₃)₂CH-benzyloxy 207 3-CF₃CF₂ 231 1-phenylethoxy 208 4-NH₂ 232 4-F, 3-CH₃-benzoyl 209 3-CH₃, 4-CH₃, 5-CH₃ 233 3-CF₃-phenyl 210 4-CH₃CH₂CH₂O 234 4-CH₃O-phenylamino 211 3-CF₃ 235 cyclopropoxy 212 2-NO₂ 236 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 237 3-isopropyl 261 3-CF₃O-benzyloxy 238 2-Cl, 3-Cl 262 3-CF₃-benzyloxy 239 3-CF₃O 263 3-F, 5-F-benzyloxy 240 4-F 264 cyclohexylmethyleneoxy 241 4-CH₃ 265 benzyloxy 242 2-F, 5-Br 266 3-CF₃, 5-CF₃-benzyloxy 243 4-Cl, 3-CH₃ 267 4-CF₃O-benzyloxy 244 3-CH₃CH₂ 268 4-CH₃CH₂-benzyloxy 245 3-CH₃, 5-CH₃ 269 isopropoxy 246 3-(CH₃)₃C 270 3-CF₃-benzyl 247 4-F, 3-CH₃ 271 isopropylthio 248 3-Cl, 4-Cl 272 cyclopentoxy 249 3,4-(CH₂)₄ 273 3-Cl-5-pyridinyloxy 250 3-HCF₂CF₂O 274 3-CF₃S-benzyloxy 251 3-CHF₂O 275 3-CH₃, 4-CH₃-benzyloxy 252 3-(CH₃)₂N 276 2-F, 3-CF₃-benzyloxy 253 3-cyclopropyl 277 3-F, S-CF₃-benzyloxy 254 3-(2-furyl) 278 4-(CH₃)₂CH-benzyloxy 255 3-CF₃CF₂ 279 1-phenylethoxy 256 4-NH₂ 280 4-F, 3-CH₃-benzoyl 257 3-CH₃, 4-CH₃, 5-CH₃ 281 3-CF₃-phenyl 258 4-CH₃CH₂CH₂O 282 4-CH₃O-phenylamino 259 3-CF₃ 283 cyclopropoxy 260 2-NO₂ 284 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 285 3-isopropyl 309 3-CF₃O-benzyloxy 286 2-Cl, 3-Cl 310 3-CF₃-benzyloxy 287 3-CF₃O 311 3-F, 5-F-benzyloxy 288 4-F 312 cyclohexylmethyleneoxy 289 4-CH₃ 313 benzyloxy 290 2-F, 5-Br 314 3-CF₃, 5-CF₃-benzyloxy 291 4-Cl, 3-CH₃CH₂ 315 4-CF₃O-benzyloxy 292 3-CH₃CH₂ 316 4-CH₃CH₂-benzyloxy 293 3-CH₃, 5-CH₃ 317 isopropoxy 294 3-(CH₃)₃C 318 3-CF₃-benzyl 295 4-F, 3-CH₃ 319 isopropylthio 296 3-Cl, 4-Cl 320 cyclopentoxy 297 3,4(CH₂)₄ 321 3-Cl-5-pyridinyloxy 298 3-HCF₂CF₂O 322 3-CF₃S-benzyloxy 299 3-CHF₂O 323 3-CH₃, 4-CH₃-benzyloxy 300 3-(CH₃)₂N 324 2-F, 3-CF₃-benzyloxy 301 3-cyclopropyl 325 3-F, 5-CF₃-benzyloxy 302 3-(2-furyl) 326 4-(CH₃)₂CH-benzyloxy 303 3-CF₃CF₂ 327 1-phenylethoxy 304 4-NH₂ 328 4-F, 3-CH₃-benzoyl 305 3-CH₃, 4-CH₃, 5-CH₃ 329 3-CF₃-phenyl 306 4-CH₃CH₂CH₂O 330 4-CH₃O-phenylamino 307 3-CF₃ 331 cyclopropoxy 308 2-NO₂ 332 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 333 3-isopropyl 357 3-CF₃O-benzyloxy 334 2-Cl, 3-Cl 358 3-CF₃-benzyloxy 335 3-CF₃O 359 3-F, 5-F-benzyloxy 336 4-F 360 cyclohexylmethyleneoxy 337 4-CH₃ 361 benzyloxy 338 2-F, 5-Br 362 3-CF₃, 5-CF₃-benzyloxy 339 4-Cl, 3-CH₃CH₂ 363 4-CF₃O-benzyloxy 340 3-CH₃CH₂ 364 4-CH₃CH₂-benzyloxy 341 3-CH₃, 5-CH₃ 365 isopropoxy 342 3-(CH₃)₃C 366 3-CF₃-benzyl 343 4-F, 3-CH₃ 367 isopropylthio 344 3-Cl, 4-Cl 368 cyclopentoxy 345 3,4-(CH₂)₄ 369 3-Cl-5-pyridinyloxy 346 3-HCF₂CF₂O 370 3-CF₃S-benzyloxy 347 3-CHF₂O 371 3-CH₃, 4-CH₃-benzyloxy 348 3-(CH₃)₂N 372 2-F, 3-CF₃-benzyloxy 349 3-cyclopropyl 373 3-F, 5-CF₃-benzyloxy 350 3-(2-furyl) 374 4-(CH₃)₂CH-benzyloxy 351 3-CF₃CF₂ 375 1-phenylethoxy 352 4-NH₂ 376 4-F, 3-CH₃-benzoyl 353 3-CH₃, 4-CH₃, 5-CH₃ 377 3-CF₃-phenyl 354 4-CH₃CH₂CH₂O 378 4-CH₃O-phenylamino 355 3-CF₃ 379 cyclopropoxy 356 2-NO₂ 380 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 381 3-isopropyl 405 3-CF₃O-benzyloxy 382 2-Cl, 3-Cl 406 3-CF₃-benzyloxy 383 3-CF₃O 407 3-F, 5-F-benzyloxy 384 4-F 408 cyclohexylmetbyleneoxy 385 4-CH₃ 409 benzyloxy 386 2-F, 5-Br 410 3-CF₃, 5-CF₃-benzyloxy 387 4-Cl, 3-CH₃CH₂ 411 4-CF₃O-benzyloxy 388 3-CH₃CH₂ 412 4-CH₃CH₂-benzyloxy 389 3-CH₃, 5-CH₃ 413 isopropoxy 390 3-(CH₃)₃C 414 3-CF₃-benzyl 391 4-F, 3-CH₃ 415 isopropylthio 392 3-Cl, 4-Cl 416 cyclopentoxy 393 3,4-(CH₂)₄ 417 3-Cl-5-pyridinyloxy 394 3-HCF₂CF₂O 418 3-CF₃S-benzyloxy 395 3-CHF₂O 419 3-CH₃, 4-CH₃-benzyloxy 396 3-(CH₃)₂N 420 2-F, 3-CF₃-benzyloxy 397 3-cyclopropyl 421 3-F, 5-CF₃-benzyloxy 398 3-(2-furyl) 422 4-(CH₃)₂CH-benzyloxy 399 3-CF₃CF₂ 423 1-phenylethoxy 400 4-NH₂ 424 4-F, 3-CH₃-benzoyl 401 3-CH₃, 4-CH₃, 5-CH₃ 425 3-CF₃-phenyl 402 4-CH₃CH₂CH₂O 426 4-CH₃O-phenylamino 403 3-CF₃ 427 cyclopropoxy 404 2-NO₂ 428 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 429 3-isopropyl 453 3-CF₃O-benzyloxy 430 2-Cl, 3-Cl 454 3-CF₃-benzyloxy 431 3-CF₃O 455 3-F, 5-F-benzyloxy 432 4-F 456 cyclohexylmethyleneoxy 433 4-CH₃ 457 benzyloxy 434 2-F, 5-Br 458 3-CF₃, 5-CF₃-benzyloxy 435 4-Cl, 3-CH₃CH₂ 459 4-CF₃O-benzyloxy 436 3-CH₃CH₂ 460 4-CH₃CH₂-benzyloxy 437 3-CH₃, 5-CH₃ 461 isopropoxy 438 3-(CH₃)₃C 462 3-CF₃-benzyl 439 4-F, 3-CH₃ 463 isopropylthio 440 3-Cl, 4-Cl 464 cyclopentoxy 441 3,4-(CH₂)₄ 465 3-Cl-5-pyridinyloxy 442 3-HCF₂CF₂O 466 3-CF₃S-benzyloxy 443 3-CHF₂O 467 3-CH₃, 4-CH₃-benzyloxy 444 3-(CH₃)₂N 468 2-F, 3-CF₃-benzyloxy 445 3-cyclopropyl 469 3-F, 5-CF₃-benzyloxy 446 3-(2-furyl) 470 4-(CH₃)₂CH-benzyloxy 447 3-CF₃CF₂ 471 1-phenylethoxy 448 4-NH₂ 472 4-F, 3-CH₃-benzoyl 449 3-CH₃, 4-CH₃, 5-CH₃ 473 3-CF₃-phenyl 450 4-CH₃CH₂CH₂O 474 4-CH₃O-phenylamino 451 3-CF₃ 475 cyclopropoxy 452 2-NO₂ 476 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 477 3-isopropyl 501 3-CF₃O-benzyloxy 478 2-Cl, 3-Cl 502 3-CF₃-benzyloxy 479 3-CF₃O 503 3-F, 5-F-benzyloxy 480 4-F 504 cyclohexylmethyleneoxy 481 4-CH₃ 505 benzyloxy 482 2-F, 5-Br 506 3-CF₃, 5-CF₃-benzyloxy 483 4-Cl, 3-CH₃CH₂ 507 4-CF₃O-benzyloxy 484 3-CH₃CH₂ 508 4-CH₃CH₂-benzyloxy 485 3-CH₃, 5-CH₃ 509 isopropoxy 486 3-(CH₃)₃C 510 3-CF₃-benzyl 487 4-F, 3-CH₃ 511 isopropylthio 488 3-Cl, 4-Cl 512 cyclopentoxy 489 3,4-(CH₂)₄ 513 3-Cl-5-pyridinyloxy 490 3-HCF₂CF₂O 514 3-CF₃S-benzyloxy 491 3-CHF₂O 515 3-CH₃, 4-CH₃-benzyloxy 492 3-(CH₃)₂N 516 2-F, 3-CF₃-benzyloxy 493 3-cyclopropyl 517 3-F, 5-CF₃-benzyloxy 494 3-(2-furyl) 518 4-(CH₃)₂CH-benzyloxy 495 3-CF₃CF₂ 519 1-phenylethoxy 496 4-NH₂ 520 4-F, 3-CH₃-benzoyl 497 3-CH₃, 4-CH₃, 5-CH₃ 521 3-CF₃-phenyl 498 4-CH₃CH₂CH₂O 522 4-CH₃O-phenylamino 499 3-CF₃ 523 cyclopropoxy 500 2-NO₂ 524 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 525 3-isopropyl 549 3-CF₃O-benzyloxy 526 2-Cl, 3-Cl 550 3-CF₃-benzyloxy 527 3-CF₃O 551 3-F, 5-F-benzyloxy 528 4-F 552 cyclohexylmethyleneoxy 529 4-CH₃ 553 benzyloxy 530 2-F, 5-Br 554 3-CF₃, 5-CF₃-benzyloxy 531 4-Cl, 3-CH₃CH₂ 555 4-CF₃O-benzyloxy 532 3-CH₃CH₂ 556 4-CH₃CH₂-benzyloxy 533 3-CH₃, 5-CH₃ 557 isopropoxy 534 3-(CH₃)₃C 558 3-CF₃-benzyl 535 4-F, 3-CH₃ 559 isopropylthio 536 3-Cl, 4-Cl 560 cyclopentoxy 537 3,4-(CH₂)₄ 561 3-Cl-5-pyridinyloxy 538 3-HCF₂CF₂O 562 3-CF₃S-benzyloxy 539 3-CHF₂O 563 3-CH₃, 4-CH₃-benzyloxy 540 3-(CH₃)₂N 564 2-F, 3-CF₃-benzyloxy 541 3-cyclopropyl 565 3-F, 5-CF₃-benzyloxy 542 3-(2-furyl) 566 4-(CH₃)₂CH-benzyloxy 543 3-CF₃CF₂ 567 1-phenylethoxy 544 4-NH₂ 568 4-F, 3-CH₃-benzoyl 545 3-CH₃, 4-CH₃, 5-CH₃ 569 3-CF₃-phenyl 546 4-CH₃CH₂CH₂O 570 4-CH₃O-phenylamino 547 3-CF₃ 571 cyclopropoxy 548 2-NO₂ 572 4-NO₂-phenylthio

Ex. Ex. No. R_(SUB1) No. R_(SUB2) 573 3-isopropyl 597 3-CF₃O-benzyloxy 574 2-Cl, 3-Cl 598 3-CF₃-benzyloxy 575 3-CF₃O 599 3-F, 5-F-benzyloxy 576 4-F 600 cyclohexylmethyleneoxy 577 4-CH₃ 601 benzyloxy 578 2-F, 5-Br 602 3-CF₃, 5-CF₃-benzyloxy 579 4-Cl, 3-CH₃CH₂ 603 4-CF₃O-benzyloxy 580 3-CH₃CH₂ 604 4-CH₃CH₂-benzyloxy 581 3-CH₃, 5-CH₃ 605 isopropoxy 582 3-(CH₃)₃C 606 3-CF₃-benzyl 583 4-F, 3-CH₃ 607 isopropylthio 584 3-Cl, 4-Cl 608 cyclopentoxy 585 3,4-(CH₂)₄ 609 3-Cl-5-pyridinyloxy 586 3-HCF₂CF₂O 610 3-CF₃S-benzyloxy 587 3-CHF₂O 611 3-CH₃, 4-CH₃-benzyloxy 588 3-(CH₃)₂N 612 2-F, 3-CF₃-benzyloxy 589 3-cyclopropyl 613 3-F, 5-CF₃-benzyloxy 590 3-(2-furyl) 614 4-(CH₃)₂CH-benzyloxy 591 3-CF₃CF₂ 615 1-phenylethoxy 592 4-NH₂ 616 4-F, 3-CH₃-benzoyl 593 3-CH₃, 4-CH₃, 5-CH₃ 617 3-CF₃-phenyl 594 4-CH₃CH₂CH₂O 618 4-CH₃O-phenylamino 595 3-CF₃ 619 cyclopropoxy 596 2-NO₂ 620 4-NO₂-phenylthio

Calculated Observed Ex. Mass Mass No. R_(SUB1) [M + H]⁺ [M + H]⁺ 621 4-F 522.1315 522.1297 622 2-Cl, 3-Cl 572.0630 572.0653 623 2-F, 5-Br 600.0420 600.0404 624 4-Cl, 3-CH₃ 551.1098 551.1101 625 3-CH₃, 5-CH₃ 532.1722 532.1705 626 3-(CH₃)₃C 560.2035 560.2055 627 4-F, 3-CH₃ 536.1471 536.1480 628 3-Cl, 4-Cl 572.0630 572.0630 629 3,4-(CH₂)₄ 558.1879 558.1881 630 3-HCF₂CF₂O 631 3-CHF₂O 632 3-(CH₃)₂N 547.1831 547.1844 633 3-cyclopropyl 634 3-(2-furyl) 635 3-CF₃CF₂ 636 3-cyclopentyl 637 4-NH₂ 519.1519 519.1529 638 3-CH₃, 4-CH₃, 5-CH₃ 546.1879 546.1901 639 4-CH₃CH₂O 547.1594 547.1594 640 3-CF₃ 641 2-NO₂ 549.1260 549.1235 642 3,4-dimethyl 531.1644 531.1649 643 3-methyl, 5-methyl 546.1879 546.1899 644 3-methyl 517.1488 517.1493 645 2,3-difluoro 540.1221 540.1182 646 4-CF₃ 572.1282 572.1268 647 2-fluoro, 3-CF₃ 590.1189 590.1184 648 2-fluoro, 4-CF₃ 590.1189 590.1155 649 2-chloro, 4-fluoro 556.0925 556.0891 650 4-n-propyl 546.1879 546.1878 651 3-chloro, 4-fluoro 556.0925 556.0932 652 2,4-difluoro 540.1221 540.1194 653 3,5-difluoro 540.1221 540.1217 654 3,4-difluoro 540.1221 540.1248 655 3-fluoro 522.1315 522.1337 656 2-chloro 538.1019 538.1021 657 2-fluoro 522.1315 522.1310 658 2,5-difluoro 540.1221 540.1255 659 4-chloro, 2-fluoro 556.0926 556.0954 660 2,4-dichloro 572.0630 572.0667 661 2-fluoro, 3-CH₃ 662 4-chloro 537.0942 537.0944 663 4-isopropyl, 3-methyl 560.2035 560.2035 664 2,3,4-trifluoro 558.1127 558.1161 665 2,3,5-trifluoro 558.1127 558.1109 666 4-propoxy 562.1828 562.1803 667 4-isopropyl 546.1879 546.1899 668 4-CF₃O— 588.1233 588.1241 669 4-butoxy 576.1958 576.1969 670 3-methyl, 4-CH₃S— 564.1443 564.1476 671 4-nitro 549.1260 549.1306 672 3-CF₃S— 673 4-chloro, 3-fluoro 556.0925 556.0933 674 3,5-dimethoxy 564.1623 564.1617 675 4-bromo 582.0716 582.0473 676 4-sec-butyl 560.2035 560.2051 677 3-fluoro-2-nitro 567.1166 567.1135 678 3-methoxy 533.1437 533.1450 679 4-bromo-2-nitro 627.0366 627.0375 680 4-cyano 529.1362 529.1364 681 4-CH₃S— 550.1209 550.1251 682 3,4-(CH═CH)₂ 554.1566 554.1578 683 4-CH₃CH₂NH— 547.1832 547.1819 684 4-propionyl 560.1672 560.1694 685 3-phenyl 580.1723 580.1772 686 4-cyclopentyl 572.2035 572.2029

Calculated Observed Ex. Mass Mass No. R_(SUB2) [M + H]⁺ [M + H]⁺ 687 6-methyl-3-pyridinyloxy 518.1440 518.1452 688 5-chloro-3-pyridinyloxy 539.0972 539.1002 689 3-pyridinyloxy 505.1362 505.1369 690 2-methyl-3-pyridinyloxy 519.1518 519.1517 691 5-indolinyloxy 543.1519 543.1630 692 4-fluoro-2-pyridinyloxy 523.1268 523.1243 693 2-cyano-3-pyridinyloxy 530.1315 530.1300 694 5-bromo-2-pyridinyloxy 583.0667 583.0405 695 3-CF₃-2-pyridinyloxy 573.1236 573.1205 696 2-pyridinylmethyleneoxy 519.1519 519.1522 697 cyclohexylmethyleneoxy 524.2036 524.2028 698 isopropoxy 470.1488 470.1565 699 cyclopentyloxy 496.1723 496.1719 700 neo-pentoxy 498.1879 498.1845 701 4-(methoxycarbonyl-butoxy 542.1777 542.1827 702 trifluoromethoxy 496.0971 496.0959 703 2-methylpropoxy 484.1723 484.1718 704 2-methoxyethoxy 486.1515 486.1537 705 2-oxobutoxy 498.1515 498.1529 706 cyclohexyloxy 510.1880 510.1910 707 (methoxycarbonyl)methoxy 500.1308 500.1297 708 4-tetrahydropyranyloxy 512.1672 512.1631 709 1-phenylethoxy 532.1723 532.1711 710 3-CF₃O-benzyloxy 602.1389 602.1380 711 3-trifluoromethyl-benzyloxy 586.1440 586.1419 712 3,5-dimethyl-benzyloxy 546.1879 546.1890 713 3-bromo-benzyloxy 596.0671 596.0641 714 3-CF₃S-benzyloxy 618.1161 618.1151 715 3,4-dimethyl-benzyloxy 546.1879 546.1881 716 3,5-difluoro-benzyloxy 554.1378 554.1390 717 2-fluoro-3-CF₃-benzyloxy 604.1346 604.1329 718 benzyloxy 518.1566 518.1578 719 3,5-(CF₃)₂-benzyloxy 654.1314 654.1308 720 3-fluoro-5-CF₃-benzyloxy 604.1346 604.1309 721 4-CF₃O-benzyloxy 602.1389 602.1383 722 3-chloro-benzyloxy 552.1176 552.1157 723 4-ethyl-benzyloxy 546.1879 546.1862 724 3-methyl-benzyloxy 532.1723 532.1692 725 2-fluoro-benzyloxy 536.1472 536.1465 726 2,3-difluoro-benzyloxy 554.1378 554.1364 727 4-isopropyl-benzyloxy 560.2036 560.2020 728 4-methyl-benzyloxy 532.1723 532.1729 729 4-bromo-benzyloxy 596.0671 596.0669 730 4-CF₃-benzyloxy 586.1440 586.1400 731 4-fluoro-benzyloxy 536.1472 536.1454 732 3-iodo-benzyloxy 644.0533 644.0517 733 4-CF₃S-benzyloxy 618.1161 618.1165 734 4-CF₂HO-benzyloxy 584.1483 584.1480 735 4-fluoro-3-CF₃-benzyloxy 604.1346 604.1336 736 2,3,5-trifluoro-benzyloxy 572.1284 572.1276 737 4-chloro-benzyloxy 552.1176 552.1188 738 2,5-difluoro-benzyloxy 554.1378 554.1350 739 3-chloro-2-fluoro-benzyloxy 570.1082 570.1069 740 2,4-(CF₃)₂-benzyloxy 654.1314 654.1321 741 3,5-dichloro-benzyloxy 586.1787 586.1378 742 3-methoxy-benzyloxy 548.1672 548.1676 743 4-cyano-benzyloxy 543.1519 543.1517 744 4-tert-butyl-benzyloxy 574.2192 574.2163 745 isopropylthio 486.1338 486.1351 746 4-nitrophenylthio 565.1032 565.1034 747 4-acetylphenylthio 562.1287 562.1261 748 (4-chloro-thien-2-yl)-methylthio 574.0512 574.0523 749 4-methoxy-phenylamino 532.1597 532.1592 750 3-methoxy-phenylamino 532.1597 532.1593 751 4-chloro-phenylamino 536.1102 536.1125 752 4-n-propyl-phenylamino 544.1961 544.1959 753 3-cyano-phenylamino 527.1444 527.1448 754 3-CF₃-benzyl 570.1413 570.1480 755 3-methyl-4-fluoro-benzyl 534.1679 534.1688 756 3-CF₃-phenyl 556.1334 556.1339 757 2,4-dichloro-phenyl 556.0681 556.0651 758 3-methoxybenzyl 532.1723 532.1705 759 4-methoxyphenyl 518.1566 518.1533 760 3-chloro-fluoro-phenyl 540.0976 540.0957 761 4-fluoro-3-methyl-benzoyl 548.1410 548.1441 762 3-chlorobenzyl 536.1227 536.1218 763 3,4-dimethylbenzyl 530.1930 530.1887 764 3,5-dichlorobenzyl 570.0838 570.0801 765 2,3,4-trifluorophenyl 542.1177 542.1152 766 3-chloro-4-fluoro-benzyl 554.1133 554.1108 767 4-fluoro-3-methyl-phenyl 520.1523 520.1494 768 3-methyl-4-chloro-benzyl 550.1384 550.1380 769 2-methylpropanoyl 482.1566 482.1576 770 4-methylthiobenzyl 548.1494 548.1503 771 4-fluorophenyl 506.1366 506.1336 772 4-chlorophenyl 522.1071 522.1049 773 3-methoxyphenyl 518.1566 518.1544 774 4-methylbenzyl 516.1774 5l6.1769 775 1-hydroxy-2-methyl-propyl 484.1723 484.1725 776 benzyl 502.1617 502.1609 777 2-CF₃-phenyl 556.1334 556.1286 778 3,4-dichlorophenyl 556.0681 556.0698 779 benzoyl 516.1410 516.1383 780 4-fluorobenzoyl 534.1315 534.1273 781 N-piperidinyl 494.1804 494.1804 782 phenyl 488.1460 488.1457 783 thien-2-yl 494.1024 494.0987

Calculated Observed Ex. Mass Mass No. R_(SUB1) R_(SUB2) [M + H]⁺ [M + H]⁺ 784 phenoxy 3-cyclopentyl 456.2150 456.2143 785 phenoxy 3-isopropoxy 446.1943 446.1936 786 phenoxy 3-CF₃S 488.1119 488.1116 787 4-F-phenoxy 3-CF₃S 505.0946 505.0927 788 4-F-phenoxy 3-sec-butoxy 478.2005 478.1880 789 phenoxy 3-(CF₃)₂COH— 554.1378 554.1385 790 4-CH₃- 3-CF₃S 502.1275 502.1261 phenoxy 791 phenoxy 3-(2-furyl) 454.1630 454.1635 792 4-F-phenoxy 3-isopropoxy 464.1849 464.1867 793 phenoxy 3-isobutyl 444.2150 444.2157 794 phenoxy 3-tert-butoxy 460.2100 460.2103 795 4-F-phenoxy 3-CH₃CH₂O— 450.1692 450.1682 796 4-F-phenoxy 3-CF₃O— 490.1253 490.1211 797 phenoxy 4-F-3-(2-furyl)- 472.1536 472.1530 798 4-F-phenoxy 3-n-propoxy- 464.1849 464.1820 799 4-F-phenoxy 3-cyclopentyloxy- 490.2005 490.1998 800 phenoxy 3-(3-furyl)- 454.1630 454.1646 801 4-F-phenoxy 3-cyclopropyl- 476.1849 476.1857 methyleneoxy 802 phenoxy 3-CF₃CH₂O— 486.1504 486.1498

Example Table 9. (3R)-4-[N-(aryl)-[(aryl)methyl]amino]- 1,1,1,2,2-pentafluoro-3-butanols.

Ex. No. R_(SUB1) 803 3-isopropyl 804 2-Cl, 3-Cl 805 3-CF₃O 806 4-F 807 4-CH₃ 808 2-F, 5-Br 809 4-Cl, 3-CH₃CH₂ 810 3-CH₃CH₂ 811 3-CH₃, 5-CH₃ 812 3-(CH₃)₃C 813 4-F, 3-CH₃ 814 3-Cl, 4-Cl 815 3,4-(CH₂)₄ 816 3-HCF₂CF₂O 817 3-CHF₂O 818 3-(CH₃)₂N 819 3-cyclopropyl 820 3-(2-furyl) 821 3-CF₃CF₂ 822 4-NH₂ 823 3-CH₃, 4-CH₃, 5-CH₃ 824 4-CH₃CH₂CH₂O 825 3-CF₃ 826 2-NO₂

Ex. No. R_(SUB2) 827 3-CF₃O-benzyloxy 828 3-CF₃-benzyloxy 829 3-F, 5-F-benzyloxy 830 cyclohexylmethyleneoxy 831 benzyloxy 832 3-CF₃, 5-CF₃-benzyloxy 833 4-CF₃O-benzyloxy 834 4-CH₃CH₂-benzyloxy 835 isopropoxy 836 3-CF₃-benzyl 837 isopropylthio 838 cyclopentoxy 839 3-Cl-5-pyridinyloxy 840 3-CF₃S-benzyloxy 841 3-CH₃, 4-CH₃-benzyloxy 842 2-F, 3-CF₃-benzyloxy 843 3-F, 5-CF₃-benzyloxy 844 4-(CH₃)₂CH-benzyloxy 845 1-phenylethoxy 846 4-F, 3-CH₃-benzoyl 847 3-CF₃-phenyl 848 4-CH₃O-phenylamino 849 cyclopropoxy 850 4-NO₂-phenylthio

Ex. No. R_(SUB1) 851 3-isopropyl 852 2-Cl, 3-Cl 853 3-CF₃O 854 4-F 855 4-CH₃ 856 2-F, 5-Br 857 4-Cl, 3-CH₃CH₂ 858 3-CH₃CH₂ 859 3-CH₃, 5-CH₃ 860 3-(CH₃)₃C 861 4-F, 3-CH₃ 862 3-Cl, 4-Cl 863 3,4-(CH₂)₄ 864 3-HCF₂CF₂O 865 3-CHF₂O 866 3-(CH₃)₂N 867 3-cyclopropyl 868 3-(2-furyl) 869 3-CF₃CF₂ 870 4-NH₂ 871 3-CH₃, 4-CH₃, 5-CH₃ 872 4-CH₃CH₂CH₂O 873 3-CF₃ 874 2-NO₂

Ex. No. R_(SUB2) 875 3-CF₃O-benzyloxy 876 3-CF₃-benzyloxy 877 3-F, 5-F-benzyloxy 878 cyclohexylmethyleneoxy 879 benzyloxy 880 3-CF₃, 5-CF₃-benzyloxy 881 4-CF₃O-benzyloxy 882 4-CH₃CH₂-benzyloxy 883 isopropoxy 884 3-CF₃-benzyl 885 isopropylthio 886 cyclopentoxy 887 3-Cl-5-pyridinyloxy 888 3-CF₃S-benzyloxy 889 3-CH₃, 4-CH₃-benzyloxy 890 2-F, 3-CF₃-benzyloxy 891 3-F, 5-CF₃-benzyloxy 892 4-(CH₃)₂CH-benzyloxy 893 1-phenylethoxy 894 4-F, 3-CH₃-benzoyl 895 3-CF₃-phenyl 896 4-CH₃O-phenylamino 897 cyclopropoxy 898 4-NO₂-phenylthio

Example Table 10. Substituted (2R)-3-[N-(aryl)- [(aryl)oxy]amino]-1,1,1-trifluoro-2-propanols.

Ex. No. R_(SUB1) 899 3-isopropyl 900 2-Cl, 3-Cl 901 3-CF₃O 902 4-F 903 4-CH₃ 904 2-F, 5-Br 905 4-Cl, 3-CH₃CH₂ 906 3-CH₃CH₂ 907 3-CH₃, 5-CH₃ 908 3-(CH₃)₃C 909 4-F, 3-CH₃ 910 3-Cl, 4-Cl 911 3,4-(CH₂)₄ 912 3-HCF₂CF₂O 913 3-CHF₂O 914 3-(CH₃)₂N 915 3-cyclopropyl 916 3-(2-furyl) 917 3-CF₃CF₂ 918 4-NH₂ 919 3-CH₃, 4-CH₃, 5-CH₃ 920 4-CH₃CH₂CH₂O 921 3-CF₃ 922 2-NO₂

Ex. No. R_(SUB2) 923 3-CF₃O-benzyloxy 924 3-CF₃-benzyloxy 925 3-F, 5-F-benzyloxy 926 cyclohexylmethyleneoxy 927 benzyloxy 928 3-CF₃, 5-CF₃-benzyloxy 929 4-CF₃O-benzyloxy 930 4-CH₃CH₂-benzyloxy 931 isopropoxy 932 3-CF₃-benzyl 933 isopropylthio 934 cyclopentoxy 935 3-Cl-5-pyridinyloxy 936 3-CF₃S-benzyloxy 937 3-CH₃, 4-CH₃-benzyloxy 938 2-F, 3-CF₃-benzyloxy 939 3-F, 5-CF₃-benzyloxy 940 4-(CH₃)₂CH-benzyloxy 941 1-phenylethoxy 942 4-F, 3-CH₃-benzoyl 943 3-CF₃-phenyl 944 4-CH₃O-phenylamino 945 cyclopropoxy 946 4-NO₂-phenylthio

Ex. No. R_(SUB1) 947 3-isopropyl 948 2-Cl, 3-Cl 949 3-CF₃O 950 4-F 951 4-CH₃ 952 2-F, 5-Br 953 4-Cl, 3-CH₃CH₂ 954 3-CH₃CH₂ 955 3-CH₃, 5-CH₃ 956 3-(CH₃)₃C 957 4-F, 3-CH₃ 958 3-Cl, 4-Cl 959 3,4-(CH₂)₄ 960 3-HCF₂CF₂O 961 3-CHF₂O 962 3-(CH₃)₂N 963 3-cyclopropyl 964 3-(2-furyl) 965 3-CF₃CF₂ 966 4-NH₂ 967 3-CH₃, 4-CF₃, 5-CH₃ 968 3-CF₃ 970 2-NO₂

Ex. No. R_(SUB2) 971 3-CF₃O-benzyloxy 972 3-CF₃-benzyloxy 973 3-F, 5-F-benzyloxy 974 cyclohexylmethyleneoxy 975 benzyloxy 976 3-CF₃, 5-CF₃-benzyloxy 977 4-CF₃O-benzyloxy 978 4-CH₃CH₂-benzyloxy 979 isopropoxy 980 3-CF₃-benzyl 981 isopropylthio 982 cyclopentoxy 983 3-Cl-5-pyridinyloxy 984 3-CF₃S-benzyloxy 985 3-CH₃, 4-CH₃-benzyloxy 986 2-F, 3-CF₃-benzyloxy 987 3-F, 5-CF₃-benzyloxy 988 4-(CH₃)₂-CH-benzyloxy 989 1-phenylethoxy 990 4-F, 3-CH₃-benzoyl 991 3-CF₃-phenyl 992 4-CH₃O-phenylamino 993 cyclcopropoxy 994 4-NO₂-phenylthio

Ex. No. R_(SUB1) 995 3-isopropyl 996 2-Cl, 3-Cl 997 3-CF₃O 998 4-F 999 4-CH₃ 1000 2-F, 5-Br 1001 4-Cl, 3-CH₃CH₂ 1002 3-CH₃CH₂ 1003 3-CH₃, 5-CH₃ 1004 3-(CH₃)₃C 1005 4-F, 3-CH₃ 1006 3-Cl, 4-Cl 1007 3,4-(CH₂)₄ 1008 3-HCF₂CF₂O 1009 3-CHF₂O 1010 3-(CH₃)₂N 1011 3-cyclopropyl 1012 3-(2-furyl) 1013 3-CF₃CF₂ 1014 4-NH₂ 1015 3-CH₃, 4-CH₃, 5-CH₃ 1016 4-CH₃CH₂CH₂O 1017 3-CF₃ 1018 2-NO₂

Ex. No. R_(SUB2) 1019 3-CF₃O-benzyloxy 1020 3-CF₃-benzyloxy 1021 3-F, 5-F-benzyloxy 1022 cyclohexylmethyleneoxy 1023 benzyloxy 1024 3-CF₃, 5-CF₃-benzyloxy 1025 4-CF₃O-benzyloxy 1026 4-CH₃CH₂-benzyloxy 1027 isopropoxy 1028 3-CF₃-benzyl 1029 isopropylthio 1030 cyclopentoxyl 1031 3-Cl-5-pyridinyloxy 1032 3-CF₃S-benzyloxy 1033 3-CH₃, 4-CH₃-benzyloxy 1034 2-F, 3-CF₃-benzyloxy 1035 3-F, 5-CF₃-benzyloxy 1036 4-(CH₃)₂CH-benzyloxy 1037 1-phenylethoxy 1038 4-F, 3-CH₃-benzoyl 1039 3-CF₃-phenyl 1040 4-CH₃O-phenylamino 1041 cyclopropoxy 1042 4-NO₂-phenylthio

Ex. No. R_(SUB1) 1043 3-isopropyl 1044 2-Cl, 3-Cl 1045 3-CF₃O 1046 4-F 1047 4-CH₃ 1048 2-F, 5-Br 1049 4-Cl, 3-CH₃CH₂ 1050 3-CH₃CH₂ 1051 3-CH₃, 5-CH₃ 1052 3-(CH₃)₃C 1053 4-F, 3-CH₃ 1054 3-Cl, 4-Cl 1055 3,4-(CH₂)₄ 1056 3-HCF₂CF₂O 1057 3-CHF₂O 1058 3-(CH₃)₂N 1059 3-cyclopropyl 1060 3-(2-furyl) 1061 3-CF₃CF₂ 1062 4-NH₂ 1063 3-CH₃, 4-CH₃, 5-CH₃ 1064 4-CH₃CH₂CH₂O 1065 3-CF₃ 1066 2-NO₂

Ex. No. R_(SUB2) 1067 3-CF₃O-benzyloxy 1068 3-CF₃-benzyloxy 1069 3-F, 5-F-benzyloxy 1070 cyclohexylmethyleneoxy 1071 benzyloxy 1072 3-CF₃, 5-CF₃-benzyloxy 1073 4-CF₃O-benzyloxy 1074 4-CH₃CH₂-benzyloxy 1075 isopropoxy 1076 3-CF₃-benzyl 1077 isopropylthio 1078 cyclopentoxy 1079 3-Cl-5-pyridinyloxy 1080 3-CF₃S-benzyloxy 1081 3-CH₃, 4-CH₃-benzyloxy 1082 2-F, 3-CF₃-benzyloxy 1083 3-F, 5-CF₃-benzyloxy 1084 4-(CH₃)₂CH-benzyloxy 1085 1-phenylethoxy 1086 4-F, 3-CH₃-benzoyl 1087 3-CF₃-phenyl 1088 4-CH₃O-phenylamino 1089 cyclopropoxy 1090 4-NO₂-phenylthio

Ex. No. R_(SUB1) 1091 3-isopropyl 1092 2-Cl, 3-Cl 1093 3-CF₃O 1094 4-F 1095 4-CH₃ 1096 2-F, 5-Br 1097 4-Cl, 3-CH₃CH₂ 1098 3-CH₃CH₂ 1099 3-CH₃, 5-CH₃ 1100 3-(CH₃)₃C 1101 4-F, 3-CH₃ 1102 3-Cl, 4-Cl 1103 3,4-(CH₂)₄ 1104 3-HCF₂CF₂O 1105 3-CHF₂O 1106 3-(CH₃)₂N 1107 3-cyclopropyl 1108 3-(2-furyl) 1109 3-CF₃CF₂ 1110 4-NH₂ 1111 3-CH₃, 4-CH₃, 5-CH₃ 1112 4-CH₃CH₂CH₂O 1113 3-CF₃ 1114 2-NO₂

Ex. No. R_(SUB2) 1115 3-CF₃O-benzyloxy 1116 3-CF₃-benzyloxy 1117 3-F, 5-F-benzyloxy 1118 cyclohexylmethyleneoxy 1119 benzyloxy 1120 3-CF₃, 5-CF₃-benzyloxy 1121 4-CF₃O-benzyloxy 1122 4-CH₃CH₂-benzyloxy 1123 isopropoxy 1124 3-CF₃-benzyl 1125 isopropylthio 1126 cyclopentoxy 1127 3-Cl-5-pyridinyloxy 1128 3-CF₃S-benzyloxy 1129 3-CH₃, 4-CH₃-benzyloxy 1130 2-F, 3-CF₃-benzyloxy 1131 3-F, 5-CF₃-benzyloxy 1132 4-(CH₃)₂CH-benzyloxy 1133 1-phenylethoxy 1134 4-F, 3-CH₃-benzoyl 1135 3-CF₃-phenyl 1136 4-CH₃O-phenylamino 1137 cyclopropoxy 1138 4-NO₂-phenylthio

Example Table 11. (2R)-3-[N-(aryl)-[(aryl)methyl]amino]- 1,1-difluoro-1-chloro-2-propanols.

Ex. No. R_(SUB1) 1139 3-isopropyl 1140 2-Cl, 3-Cl 1141 3-CF₃O 1142 4-F 1143 4-CH₃ 1144 2-F, 5-Br 1145 4-Cl, 3-CH₃CH₂ 1146 3-CH₃CH₂ 1147 3-CH₃, 5-CH₃ 1148 3-(CH₃)₃C 1149 4-F, 3-CH₃ 1150 3-Cl, 4-Cl 1151 3,4-(CH₂)₄ 1152 3-HCF₂CF₂O 1153 3-CHF₂O 1154 3-(CH₃)₂N 1155 3-cyclopropyl 1156 3-(2-furyl) 1157 3-CF₃CF₂ 1158 4-NH₂ 1159 3-CH₃, 4-CH₃, 5-CH₃ 1160 4-CH₃CH₂CH₂O 1161 3-CF₃ 1162 2-NO₂

Ex. No. R_(SUB2) 1163 3-CF₃O-benzyloxy 1164 3-CF₃-benzyloxy 1165 3-F, 5-F-benzyloxy 1166 cyclohexylmethyleneoxy 1167 benzyloxy 1168 3-CF₃, 5-CF₃-benzyloxy 1169 4-CF₃O-benzyloxy 1170 4-CH₃CH₂-benzyloxy 1171 isopropoxy 1172 3-CF₃-benzyl 1173 isopropylthio 1174 cyclopentoxy 1175 3-Cl-5-pyridinyloxy 1176 3-CF₃S-benzyloxy 1177 3-CH₃, 4-CH₃-benzyloxy 1178 2-F, 3-CF₃-benzyloxy 1179 3-F, 5-CF₃-benzyloxy 1180 4-(CH₃)₂CH-benzyloxy 1181 1-phenylethoxy 1182 4-F, 3-CH₃-benzoyl 1183 3-CF₃-phenyl 1184 4-CH₃O-phenylamino 1185 cyclopropoxy 1186 4-NO₂-phenylthio

Ex. No. R_(SUB1) 1187 3-isopropyl 1188 2-Cl, 3-Cl 1189 3-CF₃O 1190 4-F 1191 4-CH₃ 1192 2-F, 5-Br 1193 4-Cl, 3-CH₃CH₂ 1194 3-CH₃CH₂ 1195 3-CH₃, 5-CH₃ 1196 3-(CH₃)₃C 1197 4-F, 3-CH₃ 1198 3-Cl, 4-Cl 1199 3,4-(CH₂)₄ 1200 3-HCF₂CF₂O 1201 3-CHF₂O 1202 3-(CH₃)₂N 1203 3-cyclopropyl 1204 3-(2-furyl) 1205 3-CF₃CF₂ 1206 4-NH₂ 1207 3-CH₃, 4-CH₃, 5-CH₃ 1208 4-CH₃CH₂CH₂O 1209 3-CF₃ 1210 2-NO₂

Ex. No. R_(SUB2) 1211 3-CF₃O-benzyloxy 1212 3-CF₃-benzyloxy 1213 3-F, 5-F-benzyloxy 1214 cyclohexylmethyleneoxy 1215 benzyloxy 1216 3-CF₃, 5-CF₃-benzyloxy 1217 4-CF₃O-benzyloxy 1218 4-CH₃CH₂-benzyloxy 1219 isopropoxy 1220 3-CF₃-benzyl 1221 isopropylthio 1222 cyclopentoxy 1223 3-Cl-5-pyridinyloxy 1224 3-CF₃S-benzyloxy 1225 3-CH₃, 4-CH₃-benzyloxy 1226 2-F, 3-CF₃-benzyloxy 1227 3-F, 5-CF₃-benzyloxy 1228 4-(CH₃)₂CH-benzyloxy 1229 1-phenylethoxy 1230 4-F, 3-CH₃-benzoyl 1231 3-CF₃-phenyl 1232 4-CH₃O-phenylamino 1233 cyclopropoxy 1234 4-NO₂-phenylthio

Example Table 12. (2R)-3-[N,N′-(diaryl)amino]- 1,1,1-trifluoro-2-propanols.

Ex. No. R_(SUB1) 1235 3-isopropyl 1236 2-Cl, 3-Cl 1237 3-CF₃O 1238 4-F 1239 4-CH₃ 1240 2-F, 5-Br 1241 4-Cl, 3-CH₃CH₂ 1242 3-CH₃CH₂ 1243 3-CH₃, 5-CH₃ 1244 3-(CH₃)₃C 1245 4-F, 3-CH₃ 1246 3-Cl, 4-Cl 1247 3,4-(CH₂)₄ 1248 3-HCF₂CF₂O 1249 3-CHF₂O 1250 3-(CH₃)₂N 1251 3-cyclopropyl 1252 3-(2-furyl) 1253 3-CF₃CF₂ 1254 4-NH₂ 1255 3-CH₃, 4-CH₃, 5-CH₃ 1256 4-CH₃CH₂CH₂O 1257 3-CF₃ 1258 2-NO₂

Ex. No. R_(SUB2) 1259 3-CF₃O-benzyloxy 1260 3-CF₃-benzyloxy 1261 3-F, 5-F-benzyloxy 1262 cyclohexylmethyleneoxy 1263 benzyloxy 1264 3-CF₃, 5-CF₃-benzyloxy 1265 4-CF₃O-benzyloxy 1266 4-CH₃CH₂-benzyloxy 1267 isopropoxy 1268 3-CF₃-benzyl 1269 isopropylthio 1270 cyclopentoxy 1271 3-Cl-5-pyridinyloxy 1272 3-CF₃S-benzyloxy 1273 3-CH₃, 4-CH₃-benzyloxy 1274 2-F, 3-CF₃-benzyloxy 1275 3-F, 5-CF₃-benzyloxy 1276 4-(CH₃)₂CH-benzyloxy 1277 1-phenylethoxy 1278 4-F, 3-CH₃-benzoyl 1279 3-CF₃-phenyl 1280 4-CH₃O-phenylamino 1281 cyclopropoxy 1282 4-NO₂-phenylthio

Ex. No. R_(SUB1) 1283 3-isopropyl 1284 2-Cl, 3-Cl 1285 3-CF₃O 1286 4-F 1287 4-CH₃ 1288 2-F, 5-Br 1289 4-Cl, 3-CH₃CH₂ 1290 3-CH₃CH₂ 1291 3-CH₃, 5-CH₃ 1292 3-(CH₃)₃C 1293 4-F, 3-CH₃ 1294 3-Cl, 4-Cl 1295 3,4-(CH₂)₄ 1296 3-HCF₂CF₂O 1297 3-CHF₂O 1298 3-(CH₃)₂N 1299 3-cyclopropyl 1300 3-(2-furyl) 1301 3-CF₃CF₂ 1302 4-NH₂ 1303 3-CH₃, 4-CH₃, 5-CH₃ 1304 4-CH₃CH₂CH₂O 1305 3-CF₃ 1306 2-NO₂

Ex. No. R_(SUB2) 1307 3-CF₃O-benzyloxy 1308 3-CF₃-benzyloxy 1309 3-F, 5-F-benzyloxy 1310 cyclohexylmethyleneoxy 1311 benzyloxy 1312 3-CF₃, 5-CF₃-benzyloxy 1313 4-CF₃O-benzyloxy 1314 4-CH₃CH₂-benzyloxy 1315 isopropoxy 1316 3-CF₃-benzyl 1317 isopropylthio 1318 cyclopentoxy 1319 3-Cl-5-pyridinyloxy 1320 3-CF₃S-benzyloxy 1321 3-CH₃, 4-CH₃-benzyloxy 1322 2-F, 3-CF₃-benzyloxy 1323 3-F, 5-CF₃-benzyloxy 1324 4-(CH₃)₂CH-benzyloxy 1325 1-phenylethoxy 1326 4-F, 3-CH₃-benzoyl 1327 3-CF₃-phenyl 1328 4-CH₃O-phenylamino 1329 cyclopropoxy 1330 4-NO₂-phenylthio

Ex. No. R_(SUB1) 1331 3-isopropyl 1332 2-Cl, 3-Cl 1333 3-CF₃O 1334 4-F 1335 4-CH₃ 1336 2-F, 5-Br 1337 4-Cl, 3-CH₃CH₂ 1338 3-CH₃CH₂ 1339 3-CH₃, 5-CH₃ 1340 3-(CH₃)₃C 1341 4-F, 3-CH₃ 1342 3-Cl, 4-Cl 1343 3,4-(CH₂)₄ 1344 3-HCF₂CF₂O 1345 3-CHF₂O 1346 3-(CH₃)₂N 1347 3-cyclopropyl 1348 3-(2-furyl) 1349 3-CF₃CF₂ 1350 4-NH₂ 1351 3-CH₃, 4-CH₃, 5-CH₃ 1352 4-CH₃CH₂CH₂O 1353 3-CF₃ 1354 2-NO₂

Ex. No. R_(SUB2) 1355 3-CF₃O-benzyloxy 1356 3-CF₃-benzyloxy 1357 3-F, 5-F-benzyloxy 1358 cyclohexylmethyleneoxy 1359 benzyloxy 1360 3-CF₃, 5-CF₃-benzyloxy 1361 4-CF₃O-benzyloxy 1362 4-CH₃CH₂-benzyloxy 1363 isopropoxy 1364 3-CF₃-benzyl 1365 isopropylthio 1366 cyclopentoxy 1367 3-Cl-5-pyridinyloxy 1368 3-CF₃S-benzyloxy 1369 3-CH₃, 4-CH₃-benzyloxy 1370 2-F, 3-CF₃-benzyloxy 1371 3-F, 5-CF₃-benzyloxy 1372 4-(CH₃)₂CH-benzyloxy 1373 1-phenylethoxy 1374 4-F, 3-CH₃-benzoyl 1375 3-CF₃-phenyl 1376 4-CH₃O-phenylamino 1377 cyclopropoxy 1378 4-NO₂-phenylthio

Ex. No. R_(SUB1) 1379 3-isopropyl 1380 2-Cl, 3-Cl 1381 3-CF₃O 1382 4-F 1383 4-CH₃ 1384 2-F, 5-Br 1385 4-Cl, 3-CH₃CH₂ 1386 3-CH₃CH₂ 1387 3-CH₃, 5-CH₃ 1388 3-(CH₃)₃C 1389 4-F, 3-CH₃ 1390 3-Cl, 4-Cl 1391 3,4-(CH₂)₄ 1392 3-HCF₂CF₂O 1393 3-CHF₂O 1394 3-(CH₃)₂N 1395 3-cyclopropyl 1396 3-(2-furyl) 1397 3-CF₃CF₂ 1398 4-NH₂ 1399 3-CH₃, 4-CH₃, 5-CH₃ 1400 4-CH₃CH₂CH₂O 1401 3-CF₃ 1402 2-NO₂

Ex. No. R_(SUB2) 1403 3-CF₃O-benzyloxy 1404 3-CF₃-benzyloxy 1405 3-F, 5-F-benzyloxy 1406 cyclohexylmethyleneoxy 1407 benzyloxy 1408 3-CF₃, 5-CF₃-benzyloxy 1409 4-CF₃O-benzyloxy 1410 4-CH₃CH₂-benzyloxy 1411 isopropoxy 1412 3-CF₃-benzyl 1413 isopropylthio 1414 cyclopentoxy 1415 3-Cl-5-pyridinyloxy 1416 3-CF₃S-benzyloxy 1417 3-CH₃, 4-CH₃-benzyloxy 1418 2-F, 3-CF₃-benzyloxy 1419 3-F, 5-CF₃-benzyloxy 1420 4-(CH₃)₂CH-benzyloxy 1421 1-phenylethoxy 1422 4-F, 3-CH₃-benzoyl 1423 3-CF₃-phenyl 1424 4-CH₃O-phenylamino 1425 cyclopropoxy 1426 4-NO₂-phenylthio

BIOASSAYS CETP Activity In Vitro Assay of CETP Inhibition Using Purified Components

(Reconstituted Buffer Assay)

The ability of compounds to inhibit CETP activity was assessed using an in vitro assay that measured the rate of transfer of radiolabeled cholesteryl ester ([³H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn, K. C. et al. (Glenn and Melton, “Quantification of Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein,” Meth. Enzymol., 263, 339-351 (1996)). Human recombinant CETP can be obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP and purified as described by Wang, S. et al. (J. Biol. Chem. 267, 17487-17490 (1992)). To measure CETP activity, [³H]CE-labeled-HDL, LDL, CETP and assay buffer (50 mM tris(hydroxymethyl)aminomethane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine-tetraacetic acid (EDTA); 1% bovine serum albumin) were incubated in a final volume of 200 μL, for 2 hours at 37° C. in 96 well plates. Inhibitors were included in the assay by diluting from a 10 mM DMSO stock solution into 16% (v/v) aqueous DMSO so that the final concentration of inhibitor was 800 μM. The inhibitors were then diluted 1:1 with CETP in assay buffer, and then 25 μL of that solution was mixed with 175 μL of lipoprotein pool for assay. Following incubation, LDL was differentially precipitated by the addition of 50 μL of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes. A potion of the solution (200 μL) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that do not contain CETP. The rate of [³H]CE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [³H]CE transferred.

The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of [³H]CE from HDL to LDL. This value was defined as the IC₅₀. The IC₅₀ values determined from this assay are accurate when the IC₅₀ is greater than 10 nM. In the case where compounds have greater inhibitory potency, accurate measurements of IC₅₀ may be determined using longer incubation times (up to 18 hours) and lower final concentrations of CETP (<50 nM).

Examples of IC₅₀ values determined by these methods are summarized in Table 9.

Assay of CETP Inhibition in Human Plasma

Blood was obtained from healthy volunteers, recruited from the personnel of Monsanto Company, Saint Louis, MO. Blood was collected in tubes containing EDTA (EDTA plasma pool). The EDTA human plasma pool, previously stored at −20° C., was thawed at room temperature and centrifuged for 5 minutes to remove any particulate matter. Tritiated HDL, radiolabeled in the cholesteryl ester moiety ([³H]CE-HDL) as described by Morton and Zilversmit (J. Biol. Chem., 256, 11992-95 (1981)), was added to the plasma to a final concentration of 25 μg/mL cholesterol. Equal volumes (396 μL) of the plasma containing the [³H]CE-HDL were added by pipette into micro tubes (Titertube®, Bio-Rad laboratories, Hercules, Calif.). Inhibitor compounds, dissolved as 20-50 mM stock solutions in DMSO, were serially diluted in DMSO (or an alternative solvent in some cases, such as dimethylformamide or ethanol). Four μL of each of the serial dilutions of inhibitor compounds or DMSO alone were then added to each of the tubes containing plasma (396 μL). After mixing, triplicate aliquots (100 μL) from each plasma tube were then transferred to wells of 96-well round-bottomed polystyrene microtiter plates (Corning, Coming, N.Y.). Plates were sealed with plastic film and incubated at 37° C. for 4 hours. “Test” samples contained plasma with dilutions of inhibitor compounds. “Control” samples contained plasma with DMSO diluted to the same concentration as the test samples, but without inhibitor. “Blank” samples were prepared as “control” samples, but were left in the micro tubes at 4° C. for the 4 hour incubation and were then added to the microtiter wells at the end of the incubation period. VLDL and LDL were precipitated by the addition of 10 μL of precipitating reagent (1% (w/v) dextran sulfate (Dextralip50)/0.5 M magnesium chloride, pH 7.4) to all wells. The wells were mixed on a plate mixer and then incubated at ambient temperature for 10 min. The plates were then centrifuged at 1000×g for 30 min at 10° C. The supernatants (50 μL) from each well were then transferred to Picoplate™ 96 plate wells (Packard, Meriden, Conn.) containing Microscint™-40 (Packard, Meriden, Conn.). The plates were heat-sealed (TopSeal™-P, Packard, Meriden, Conn.) according to the manufacturer's directions and mixed for 30 min. Radioactivity was measured on a microplate scintillation counter (TopCount, Packard, Meriden, Conn.). The maximum percentage transfer in the control wells (% transfer) was determined using the following equation: ${\% \quad {Transfer}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{control}} \right\rbrack \times 100}{{dpm}_{blank}}$

The percentage of transfer relative to the control (% control) was determined in the wells containing inhibitor compounds was determined as follows: ${\% \quad {Control}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{test}} \right\rbrack \times 100}{{dpm}_{blank} - {dpm}_{control}}$

IC₅₀ values were then calculated from plots of % control versus concentration of inhibitor compound. IC₅₀ values were determined as the concentration of inhibitor compound inhibiting transfer of [³H]CE from the supernatant [³H]CE-HDL to the precipitated VLDL and LDL by 50% compared to the transfer obtained in the control wells.

Examples of plasma IC₅₀ values determined by these methods are summarized in Table 10.

Assay of CETP Inhibition In Vivo

Inhibition of CETP activity by a test compound can be determined by administering the compound to an animal by intravenous injection or oral gavage, measuring the amount of transfer of tritium-labeled cholesteryl ester ([³H]CE) from HDL to VLDL and LDL particles, and comparing this amount of transfer with the amount of transfer observed in control animals.

Male golden Syrian hamsters were maintained on a diet of chow containing 0.24% cholesterol for at least two weeks prior to the study. For 15 animals receiving intravenous dosing immediately before the experiment, animals were anesthetized with pentobarbital. Anesthesia was maintained throughout the experiment. In-dwelling catheters were inserted into the jugular vein and carotid artery. At the start of the experiment all animals received 0.2 mL of a solution containing [³H]CE-HDL into the jugular vein. [³H]CE-HDL is a preparation of human HDL containing tritium-labeled cholesteryl ester, and was prepared according to the method of Glenn et al. (Meth. Enzymol., 263, 339-351 (1996)). Test compound was dissolved as a 80 mM stock solution in vehicle (2% ethanol: 98% PEG 400, Sigma Chemical Company, St. Louis, Mo., USA) and administered either by bolus injection or by continuous infusion. Two minutes after the [³H]CE-HDL dose was administered, animals received 0.1 mL of the test solution injected into the jugular vein. Control animals received 0.1 mL of the intravenous vehicle solution without test compound. After 5 minutes, the first blood samples (0.5 mL) were taken from the carotid artery and collected in standard microtainer tubes containing ethylenediamine tetraacetic acid. Saline (0.5 mL) was injected to flush the catheter and replace blood volume. Subsequent blood samples were taken at two hours and four hours by the same method. Blood samples were mixed well and kept on ice until the completion of the experiment. Plasma was obtained by centrifugation of the blood samples at 4° C. The plasma (50 μL) was treated with 5 μL of precipitating reagent (dextran sulfate, 10 g/L; 0.5 M magnesium chloride) to remove VLDL/LDL. After centrifugation, the resulting supernatant (25 μL) containing the HDL was analyzed for radioactivity using a liquid scintillation counter.

The percentage [³H]CE transferred from HDL to LDL and VLDL (% transfer) was calculated based on the total radioactivity in equivalent plasma samples before precipitation. Typically, the amount of transfer from HDL to LDL and VLDL in control animals was 20% to 35% after 4 hours. The polyethylene glycol vehicle was determined to have no effect on CETP activity in this model.

Alternatively, conscious, non-anesthetized animals received an oral gavage dose of test compound as a suspension in 0.1% methyl cellulose in water. At a time determined for each compound at which plasma levels of the test substance reached their peak (C_(max)) after oral dosing, the animals were anesthetized with pentobarbital and then dosed with 0.2 mL of a solution containing [³H]CE-HDL into the jugular vein as described above. Control animals received 0.25 mL of the vehicle solution without test compound by oral gavage. After 4 hours, the animals were sacrificed, blood samples were collected, and the percentage [³H]CE transferred from HDL to LDL and VLDL (% transfer) assayed, as described above. The aqueous methyl cellulose vehicle was determined to have no effect on CETP activity in this model. Results from testing in this model are summarized in Table 11.

Alternatively, inhibition of CETP activity by a test compound was determined by administering the compound to mice which have been selected for expression of human CETP (HCETP) by transgenic manipulation (hCETP mice). Test compounds were administered by intravenous injection, or oral gavage and the amount of transfer of tritium-labeled cholesteryl ester ([³H]CE) from HDL to VLDL and LDL particles was determined, and compared to the amount of transfer observed in control animals. C57Bl/6 mice that were homozygous for the hCETP gene were maintained on a high fat chow diet, such as TD 88051, as described by Nishina et al. (J Lipid Res., 31, 859-869 (1990)) for at least two weeks prior to the study. Mice received an oral gavage dose of test compound as a suspension in 0.1% methyl cellulose in water or an intravenous bolus injection of test compound in 10% ethanol and 90% polyethylene glycol. Control animals received the vehicle solution without test compound by oral gavage or by an intravenous bolus injection. At the start of the experiment all animals received 0.05 mL of a solution containing [³H]CE-HDL into the tail vein. [³H]CE-HDL is a preparation of human HDL containing tritium-labeled cholesteryl ester, and was prepared according to the method of Glenn et al. (Meth. Enzymol., 263, 339-351 (1996)). After 30 minutes, the animals were exsanguinated and blood collected in standard microtainer tubes containing ethylenediamine tetraacetic acid. Blood samples were mixed well and kept on ice until the completion of the experiment. Plasma was obtained by centrifugation of the blood samples at 4° C. The plasma was separated and analyzed by gel filtration chromatography and the relative proportion of [³H]CE in the VLDL, LDL and HDL regions was determined.

The percentage [³H]CE transferred from HDL to LDL and VLDL (% transfer) was calculated based on the total radioactivity in equivalent plasma samples before precipitation. Typically, the amount of transfer from HDL to LDL and VLDL in control animals was 20% to 35% after 30 min. The polyethylene glycol and the aqueous methyl cellulose vehicles were determined to have no effect on CETP activity in this model. Results from testing in this model are summarized in Table 12.

Assay of Plasma HDL Elevation In Vivo

Syrian Golden hamsters were made hypercholesterolemic by feeding cholesterol supplemented chow for a minimum of two weeks, as described above. Test compounds were administered orally in selected aqueous or oil based vehicles for up to 1 week. Serum was obtained and analyzed by precipitation or size exclusion chromatography for the relative abundance of VLDL, LDL and HDL. Results from testing in this model are summarized in Table 13.

Alternatively, a strain of C57bl mouse was made to transgenicaly express human CETP. Plasma concentrations of hCETP ranged from 2-20 μg/ml. The hCETP mice were made hypercholesterolemic by feeding cholesterol and fat supplemented chow for a minimum of two weeks, as described above. Test compounds were administered orally in selected aqueous or oil based vehicles for up to 1 week. Serum was obtained and analyzed by size exclusion chromatography for the relative abundance of VLDL, LDL and HDL. Results from testing in this model are summarized in Table 14.

Alternatively, cynomologous monkeys were maintained on a normal chow diet. The compound corresponding to example 8 was dissolved in a corn oil based vehicle and administered by oral gavage at 10 mpk q.d. for up to 11 days. Plasma levels of drug were detected throughout the experiment in treated animals at ranges of 0.1-1.5 μg/mL. Periodically, plasma samples were taken and analyzed for total cholesterol and HDL. After seven days, the treated animals exhibited a 2% increase in HDL and a 5% increase in total cholesterol, relative to vehicle-treated controls.

Alternatively, rabbits were maintained on a normal chow diet. The compound corresponding to example 8 was dissolved in a vehicle of ethanol:propylene glycol (1.5:18) and administered by Alzet pump at 30 mg/day/animal for up to 14 days. Plasma concentrations of drug were detected throughout the duration of the pump infusion in treated animals and averaged 1.2 μg/mL. Periodically, plasma samples were taken and analyzed for triglycerides, total cholesterol, and HDL. After fourteen days, the treated animals exhibited a 12% decrease in HDL, a 19% decrease in total cholesterol, as well as a 17% increase in triglycerides, compared to pre-dose levels.

TABLE 9 Inhibition of CETP Activity by Examples in Reconstituted Buffer Assay. Ex. IC₅₀ No. (μM)  8 0.0008 11 0.001 19 0.004  9 0.008 10 0.012  2 0.014  4 0.014 20 0.027 22 0.027 12 0.034 14 0.04 18 0.044 16 0.049 43 0.058 23 0.066 34 0.076 41 0.086 21 0.11 13 0.13  1 0.14 33 0.15 38 0.18 36 0.20 37 0.21 40 0.23 35 0.28 24 0.33 42 0.38 27 0.44 26 0.53 29 0.72  3 0.76 28 0.86 32 1.2 25 1.4 39 1.6 15 1.6 30 2.7   33B 3.2  5 3.4 31 3.5  7 4.9 44 6.8 17 18  6 68 ^( 44A) >50

TABLE 10 Inhibition of CETP Activity by Examples in Human Plasma Assay. Ex. IC₅₀ No. (μM) 8 0.049 11 0.072 10 0.11 22 0.14 19 0.19 20 0.3 18 0.44 14 0.59 9 0.62 2 0.65 4 0.65 16 0.77 12 0.79 34 1.4 43 1.5 23 2.0 1 5.6 41 7.2 42 11 3 20

TABLE 11 Inhibition of CETP-mediated Transfer in Hamster Ex. Single Oral % Inhibition No. Dose of Transfer 8 10 mpk 35

TABLE 12 Inhibition of CETP-mediated Transfer in hCETP Mice. Ex. Single Oral % Inhibition No. Dose of Transfer 8 60 mpk 40

TABLE 13 Change in Lipoprotein Profile in Hamster. Oral Dose % Change in Ex. qd, Lipoprotein Profile No. 5 days HDL LDL VLDL 8 30 mpk 12 −12 −22

TABLE 14 Change in Lipoprotein Profile in hEBTP Mice. Oral Dose % Change in Ex. qd, Lipoprotein Profile No. 5 days HDL LDL VLDL 8 30 mpk 12 20 — 

What we claim is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl with the proviso that R₁ is selected to have the highest Cahn-Ingold-Prelog stereochemical system ranking of three groups bonded to the hydroxy-substituted carbon to which R₁ and R₂ are attached in radical Ia:

 which radical Ia is a fragment of Formula I; R₂ is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl; R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamido, and carboxamidoalkyl; Y is selected from the group consisting of a bond, C(R₁₄)₂, O, C(O), and N(R₁₄) with the proviso that Y is O, C(O), or N(R₁₄) when Z is a bond or C(R₁₅)₂; R₁₄ and R₁₅ are independently hydrido or alkyl; Z is selected from the group consisting of a bond, C(R₁₅)₂, O, C(O), and N(R₁₅) with the proviso that Z is O, C(O), or N(R₁₅) when Y is a bond or C(R₁₄)₂; R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano; R₅ and R₆ are optionally taken together to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 or 6 members, and an aryl ring, wherein said cycloalkenyl ring, said partially saturated heterocyclyl ring, said heteroaryl ring, and said aryl are optionally substituted by one or more substituents selected from the group consisting of R₁₀, R₁₁, and R₁₂; R₁₀ and R₁₁ are optionally taken together to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 or 6 members, and an aryl ring, wherein said cycloalkenyl ring, said partially saturated heterocyclyl ring, said heteroaryl ring, and said aryl is optionally substituted by one or more substituents selected from the group consisting of R₅, R₆, and R₇; with the proviso that the groups R₅ and R₆ and the groups R₁₀ and R₁₁ are not simultaneously taken together to form two rings; with the further proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido or with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 2. Compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 3. Compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl with the proviso that R₁ is selected to have the highest Cahn-Ingold-Prelog stereochemical system ranking of said three groups bonded to the hydroxy-substituted carbon to which R₁ and R₂ are attached in said fragment of the Formula I and with the further proviso that said haloalkyl has two or more halo substituents; R₂ is hydrido; R₃ is hydrido; Y is selected from the group consisting of a NH, O, and C(O); Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylamino, alkylthio, arylamino, arylthio, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 4. Compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein; n is 1; R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is NH or O; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chlorofluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chlorofluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylanino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylanino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyi, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamnino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamnino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrfluoroethoxy, trifluoromethyl, and trifluoromethoxy; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 5. Compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein; n is 1; R₁ is selected from the group consisting of trifluoromethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is O; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chlorofluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 6. Compound of claim 3 of Formula II:

or a pharmaceutically acceptable salt thereof, wherein; R₁ is haloalkyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylthio, arylamino, arylthio, arylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 7. Compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 8. Compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrauoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of 1,1,2,2-tetrafluoroethoxy, pentafluoroethyl, and trifluoromethyl; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 9. Compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is a compound of Formula III:

wherein R₅ and R₁₀ are selected to form a compound selected from the group consisting of; R₅ is 3-isopropylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 4methylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-ethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-t-butylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is heptafluoropropyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4aminophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4propoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-nitro phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-difluorobenzyloxy and R₁₀ is heptafluoropropyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is heptafluoropropyl; R₅ is benzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-ethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is isopropoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is heptafluoropropyl; R₅ is isopropylthio and R₁₀ is heptafluoropropyl; R₅ is cyclopentoxy and R₁₀ is heptafluoropropyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 1-phenylethoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is heptafluoropropyl; R₅ is 4-methoxyphenylamino and R₁₀ is heptafluoropropyl; R₅ is 4-nitrophenylthio and R₁₀ is heptafluoropropyl; R₅ is 3-isopropylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-methylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-ethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-t-butylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is pentafluoroethyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-aminophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-propoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2-nitrophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is pentafluoroethyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is pentafluoroethyl; R₅ is benzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-ethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is isopropoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is pentafluoroethyl; R₅ is isopropylthio and R₁₀ is pentafluoroethyl; R₅ is cyclopentoxy and R₁₀ is pentafluoroethyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 1-phenylethoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is pentafluoroethyl; R₅ is 4-methoxyphenylamino and R₁₀ is pentafluoroethyl; R₅ is 4-nitrophenylthio and R₁₀ is pentafluoroethyl; R₅ is 3-isopropylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluorophenoxy and R₁₀ is trifluoromethyl; R₅ is 4-methylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is trifluoromethyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-ethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-dimethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-t-butylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is trifluoromethyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is trifluoromethyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is trifluoromethyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is trifluoromethyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-aminophenoxy and R₁₀ is trifluoromethyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-propoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2-nitrophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is trifluoromethyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is trifluoromethyl; R₅ is benzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-ethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is isopropoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is trifluoromethyl; R₅ is isopropylthio and R₁₀ is trifluoromethyl; R₅ is cyclopentoxy and R₁₀ is trifluoromethyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 2-fluoro-3-trifluoropethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 1-phenylethoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is trifluoromethyl; R₅ is 4-methoxyphenylamino and R₁₀ is trifluoromethyl; R₅ is 4-nitrophenylthio and R₁₀ is trifluoromethyl; R₅ is 3-isopropylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2,3-dichlorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-methylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-ethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-dimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-t-butylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,4-dichlorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is trifluoromethoxy; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-dimethylaminophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-cyclopropylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-(2-furyl)phenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-aminophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-propoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylphenoxy and R₁₀ is trifluoromethoxy; R₅is 2-nitrophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-difluorobenzyloxy and R₁₀ is trifluoromethoxy; R₅ is cyclohexylmethyleneoxy and R₁₀ is trifluoromethoxy; R₅ is benzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-ethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is isopropoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylbenzyl and R₁₀ is trifluoromethoxy; R₅ is isopropylthio and R₁₀ is trifluoromethoxy; R₅ is cyclopentoxy and R₁₀ is trifluoromethoxy; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-isopropylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 1-phenylethoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylphenyl and R₁₀ is trifluoromethoxy; R₅ is 4-methoxyphenylamino and R₁₀ is trifluoromethoxy; R₅ is 4-nitrophenylthio and R₁₀ is trifluoromethoxy; R₅ is 3-isopropylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2,3-dichlorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-methylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-ethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-dimethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-t-butylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4-dichlorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-dimethylaminophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-cyclopropylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-(2-furyl)phenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-aminophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-propoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-nitro phenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-difluorobenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is cyclohexylmethyleneoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is benzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-ethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is isopropoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylbenzyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is isopropylthio and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is cyclopentoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-fluoro-5-trifluoromethylbenzyoxy and R₁₀ is 1,2,2-tetrafluoroethoxy; R₅ is 4-isopropylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 1-phenylethoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylphenyl and R₁₀ is 1,2,2-tetrafluoroethoxy; R₅ is 4-methoxyphenylamino and R₁₀ is 1,1,2,2-tetrafluoroethoxy; and R₅ is 4-nitrophenylthio and R₁₀ is 1,1,2,2-tetrafluoroethoxy.
 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, said compound being of Formula I:

wherein; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl with the proviso that R₁ is selected to have the highest Cahn-Ingold-Prelog stereochemical system ranking of three groups bonded to the hydroxy-substituted carbon to which R₁ and R₂ are attached in radical Ia:

 which radical Ia is a fragment of Formula I; R₂ is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl; R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamido, and carboxamidoalkyl; Y is selected from the group consisting of a bond, C(R₁₄)₂, O, C(O), and N(R₁₄) with the proviso that Y is O, C(O), or N(R₁₄) when Z is a bond or C(R₁₅)₂; R₁₄ and R₁₅ are independently hydrido or alkyl; Z is selected from the group consisting of a bond, C(R₁₅)₂, O, C(O), and N(R₁₅) with the proviso that Z is O, C(O), or N(R₁₅) when Y is a bond or C(R₁₄)₂; R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxanrido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonarnido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano; R₅ and R₆ are optionally taken together to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 or 6 members, and an aryl ring, wherein said cycloalkenyl ring, said partially saturated heterocyclyl ring, said heteroaryl ring, and said aryl are optionally substituted by one or more substituents selected from the group consisting of R₁₀, R₁₁, and R₁₂; R₁₀ and R₁₁ are optionally taken together to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 or 6 members, and an aryl ring, wherein said cycloalkenyl ring, said partially saturated heterocyclyl ring, said heteroaryl ring, and said aryl is optionally substituted by one or more substituents selected from the group consisting of R₅, R₆, and R₇; with the proviso that the groups R₅ and R₆ and the groups R₁₀ and R₁₁ are not simultaneously taken together to form two rings; with the further proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido or with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 11. The pharmaceutical composition of claim 10, wherein said compound is of Formula I, wherein at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 12. The pharmaceutical composition of claim 11, wherein said compound is of Formula I, wherein; nis 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl with the proviso that R₁ is selected to have the highest Cahn-Ingold-Prelog stereochemical system ranking of said three groups bonded to the hydroxy-substituted carbon to which R₁ and R₂ are attached in said fragment of the Formula I and with the further proviso that said haloalkyl has two or more halo substituents; R₂ is hydrido; R₃ is hydrido; Y is selected from the group consisting of a NH, O, and C(O); Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylamino, alkylthio, arylamino, arylthio, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 13. The pharmaceutical composition of claim 12, wherein said compound is of Formula I, wherein; n is 1; R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is NH or O; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chlorofluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloroethylphenoxy, 3-chloromethylphenoxy, 3-chlorofluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichiorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl, thiazol-5-yl, thiophen-2-yl-2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifuoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromlnethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trriluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,2-trifluorophenyl, 2,3,3-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafhuoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 14. The pharmaceutical composition of claim 13, wherein said compound is of Formula I, wherein; n is 1; R₁ is selected from the group consisting of trifluoromethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is O; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoromethylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 15. The pharmaceutical composition of claim 12, wherein said compound is of Formula II:

wherein; R₁ is haloalkyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylthio, arylamino, arylthio, arylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 16. The pharmaceutical composition of claim 15 wherein said compound is of Formula II, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifuoromethylthiophenoxy; R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1, -bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 17. The pharmaceutical composition of claim 16, wherein said compound is of Formula II, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of 1,1,2,2-tetrafluoroethoxy, pentafluoroethyl, and trifluoromethyl; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 18. The pharmaceutical composition of claim 10, wherein said compound is a compound of Formula III:

wherein R₅ and R₁₀ are selected to form a compound selected from the group consisting of; R₅ is 3-isopropylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-diclorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-methylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-ethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-t-butylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is heptafluoropropyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-aminophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-propoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-nitrophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is heptafluoropropyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is heptafluoropropyl; R₅ is benzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-ethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is isopropoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is heptafluoropropyl; R₅ is isopropylthio and R₁₀ is heptafluoropropyl; R₅ is cyclopentoxy and R₁₀ is heptafluoropropyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 1-phenylethoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluoro-3-methylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is heptafluoropropyl; R₅ is 4-methoxyphenylamino and R₁₀ is heptafluoropropyl; R₅ is 4-nitrophenylthio and R₁₀ is heptafluoropropyl; R₅ is 3-isopropylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-methylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-ethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-t-butylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is pentafluoroethyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-aminophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-propoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2-nitrophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is pentafluoroethyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is pentafluoroethyl; R₅ is benzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-ethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is isopropoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is pentafluoroethyl; R₅ is isopropylthio and R₁₀ is pentafluoroethyl; R₅ is cyclopentoxy and R₁₀ is pentafluoroethyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is pentafluomethyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-isopropylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 1-phenylethoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluoro-3-methylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is pentafluoroethyl; R₅ is 4-methoxyphenylamino and R₁₀ is pentafluoroethyl; R₅ is 4-nitrophenylthio and R₁₀ is pentafluoroethyl; R₅ is 3-isopropylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluorophenoxy and R₁₀ is trifluoromethyl; R₅ is 4-methylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is trifluoromethyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-ethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-t-butylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is trifluoromethyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is trifluoromethyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is trifluoromethyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is trifluoromethyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-aminophenoxy and R₁₀ is trifluoromethyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-propoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2-nitrophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is trifluoromethyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is trifluoromethyl; R₅ is benzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-ethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is isopropoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is trifluoromethyl; R₅ is isopropylthio and R₁₀ is trifluoromethyl; R₅ is cyclopentoxy and R₁₀ is trifluoromethyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 1-phenylethoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluoro-3-methylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is trifluoromethyl; R₅ is 4-methoxyphenylamino and R₁₀ is trifluoromethyl; R₅ is 4-nitrophenylthio and R₁₀ is trifluoromethyl; R₅ is 3-isopropylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2,3-dichlorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-methylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-dimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-t-butylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,4-dichlorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is trifluoromethoxy; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-dimethylaminophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-cyclopropylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-(2-furyl)phenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-aminophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-propoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2-nitrophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-difluorobenzyloxy and R₁₀ is trifluoromethoxy; R₅ is cyclohexylmethyleneoxy and R₁₀ is trifluoromethoxy; R₅ is benzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-ethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is isopropoxy and R₁₀ is trifluoromethoxy; R₅is 3-trifluoromethylbenzyl and R₁₀ is trifluoromethoxy; R₅ is isopropylthio and R₁₀ is trifluoromethoxy; R₅ is cyclopentoxy and R₁₀ is trifluoromethoxy; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-isopropylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 1-phenylethoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluoro-3-methylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylphenyl and R₁₀ is trifluoromethoxy; R₅ is 4-methoxyphenylamino and R₁₀ is trifluoromethoxy; R₅ is 4-nitrophenylthio and R₁₀ is trifluoromethoxy; R₅ is 3-isopropylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2,3-dichlorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-methylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-ethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-dimethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-t-butylphenoxy and R₁₀ is 1,1,2,2-tetrafuoroethoxy; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4-dichlorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-dimethylaminophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-cyclopropylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-(2-furyl)phenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-aminophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-propoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-nitrophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-difluorobenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is cyclohexylmethyleneoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is benzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-ethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is isopropoxy and R₁₀ is 1,1,2,2-tetafluoroethoxy; R₅ is 3-trifluoromethylbenzyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is isopropylthio and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is cyclopentoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-isopropylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 1-phenylethoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluoro-3-methyl benzoyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylphenyl and R₁₀ is 1,1,2,2-tetrafluoroetboxy; R₅ is 4-methoxyphenylamino and R₁₀ is 1,1,2,2-tetrafluoroethoxy; and R₅ is 4-nitrophenylthio and R₁₀ is 1,1,2,2-tetrafluoroethoxy.
 19. A method of treating or preventing a CETP-mediated disorder in a subject by administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, said compound being of Formula I:

or a pharmaceutically acceptable salt thereof, wherein; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl with the proviso that R₁ is selected to have the highest Cahn-Ingold-Prelog stereochemical system ranking of three groups bonded to the hydroxy-substituted carbon to which R₁ and R₂ are attached in radical Ia:

 which radical Ia is a fragment of Formula I; R₂ is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl; R₃ is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamido, and carboxamidoalkyl; Y is selected from the group consisting of a bond, C(R₁₄)₂, O, C(O), and N(R₁₄) with the proviso that Y is O, C(O), or N(R₁₄) when Z is a bond or C(R₁₅)₂; R₁₄ and R₁₅ are independently hydrido or alkyl; Z is selected from the group consisting of a bond, C(R₁₅)₂, O, C(O), and N(R₁₅) with the proviso that Z is O, C(O), or N(R₁₅) when Y is a bond or C(R₁₄)₂; R₄, R₈, R₉, and R₁₃ are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, alkylarnino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano; R₅ and R₆ are optionally taken together to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 or 6 members, and an aryl ring, wherein said cycloalkenyl ring, said partially saturated heterocyclyl ring, said heteroaryl ring, and said aryl are optionally substituted by one or more substituents selected from the group consisting of R₁₀, R₁₁, and R₁₂; R₁₀ and R₁₁ are optionally taken together to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 or 6 members, and an aryl ring, wherein said cycloalkenyl ring, said partially saturated heterocyclyl ring, said heteroaryl ring, and said aryl is optionally substituted by one or more substituents selected from the group consisting of R₅, R₆, and R₇; with the proviso that the groups R₅ and R₆ and the groups R₁₀ and R₁₁ are not simultaneously taken together to form two rings; with the further proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido or with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 20. The method of claim 19, wherein said compound is of Formula I, wherein at least one of R₄, R₅, R₆, R₇, and R₈ that is not hydrido and at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ that is not hydrido.
 21. The method of claim 20, wherein said compound is of Formula I, wherein; n is 1 or 2; R₁ is haloalkyl or haloalkoxyalkyl with the proviso that R₁ is selected to have the highest Cahn-Ingold-Prelog stereochemical system ranking of said three groups bonded to the hydroxy-substituted carbon to which R₁ and R₂ are attached in said fragment of the Formula I and with the further proviso that said haloalkyl has two or more halo substituents; R₂ is hydrido; R₃ is hydrido; Y is selected from the group consisting of a NH, O, and C(O); Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylamino, alkylthio, arylamino, arylthio, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, aryl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 22. The method of claim 21, wherein said compound is of Formula I, wherein; n is 1; R₁ is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is NH or O; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of 4cahinophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chlorofluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloroethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 3-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 23. The method of claim 22, wherein said compound is of Formula I, wherein; n is 1; R₁ is selected from the group consisting of trifluoromethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl; R₂ is hydrido; R₃ is hydrido; Y is O; Z is a bond; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ and R₁₀ are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy,4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamnino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3, -trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio; R₆ and R₁₁ are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl; R₇ and R₁₂ are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
 24. The method of claim 21, wherein said compound is of Formula II:

wherein; R₁ is haloalkyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or halo; R₅, R₆, R₇, R₁₀, R₁₁, and R₁₂ are independently selected from the group consisting of hydrido, perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, heteroaralkoxy, aralkyl, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, alkylthio, arylamino, arylthio, arylsulfonyl, aroyl, alkyl, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxyalkyl, and heteroaryloxy; with the proviso that at least one of R₄, R₅, R₆, R₇, and R₈ is not hydrido and with the further proviso that at least one of R₉, R₁₀, R₁₁, R₁₂, and R₁₃ is not hydrido.
 25. The method of claim 24, wherein said compound is of Formula II, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio; R₆, R₇, R₁₁ and R₁₂ are independently hydrido or fluoro.
 26. The method of claim 25, wherein said compound is of Formula II, wherein; R₁ is trifluoromethyl; R₄, R₈, R₉, and R₁₃ are independently hydrido or fluoro; R₅ is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy; R₁₀ is selected from the group consisting of 1,1,2,2-tetrafluoroethoxy, pentafluoroethyl, and trifluoromethyl; R₆, R₇, R₁₁, and R₁₂ are independently hydrido or fluoro.
 27. The method of claim 19, wherein said compound is a pound of Formula III:

wherein R₅ and R₁₀ are selected to form a compound selected from the group consisting of; R₅is 3-isopropyiphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2,3-dichsorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-methylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-ethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-t-butylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is heptafluoropropyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is heptafluoropropyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-dimethylamninophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-aminophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 4-propoxyphenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is heptafluoropropyl; R₅ is 2-nitrophenoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is heptafluoropropyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is heptafluoropropyl; R₅ is benzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-ethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is isopropoxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is heptafluoropropyl; R₅ is isopropylthio and R₁₀ is heptafluoropropyl; R₅ is cyclopentoxy and R₁₀ is heptafluoropropyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is heptafluoropropyl; R₅ is 1-phenylethoxy and R₁₀ is heptafluoropropyl; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is heptafluoropropyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is heptafluoropropyl; R₅ is 4-methoxyphenylamino and R₁₀ is heptafluoropropyl; R₅ is 4-nitrophenylthio and R₁₀ is heptafluoropropyl; R₅ is 3-isopropylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-methylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-ethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-t-butylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is pentafluoroethyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is pentafluoroethyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-dimethylamninophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-aminophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 4-propoxyphenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is pentafluoroethyl; R₅ is 2-nitrophenoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is pentafluoroethyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is pentafluoroethyl; R₅ is benzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-ethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is isopropoxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is pentafluoroethyl; R₅ is isopropylthio and R₁₀ is pentafluoroethyl; R₅ is cyclopentoxy and R₁₀ is pentafluoroethyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is pentafluoroethyl; R₅ is 4-isopropylbenzyloxy and R₁₀is pentafluoroethyl; R₅ is 1-phenylethoxy and R₁₀ is pentafluoroethyl; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is pentafluoroethyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is pentafluoroethyl; R₅ is 4-methoxyphenylamino and R₁₀ is pentafluoroethyl; R₅ is 4-nitrophenylthio and R₁₀ is pentafluoroethyl; R₅ is 3-isopropylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2,3-dichlorophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluorophenoxy and R₁₀ is trifluoromethyl; R₅ is 4-methylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is trifluoromethyl; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-ethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3,5-dimethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-t-butylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3,4-dichlorophenoxy and R₁₀ is trifluoromethyl; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is trifluoromethyl; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is trifluoromethyl; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-dimethylaminophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-cyclopropylphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-(2-furyl)phenoxy and R₁₀ is trifluoromethyl; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-aminophenoxy and R₁₀ is trifluoromethyl; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 4-propoxyphenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylphenoxy and R₁₀ is trifluoromethyl; R₅ is 2-nitrophenoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,5-difluorobenzyloxy and R₁₀ is trifluoromethyl; R₅ is cyclohexylmethyleneoxy and R₁₀ is trifluoromethyl; R₅ is benzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-ethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is isopropoxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylbenzyl and R₁₀ is trifluoromethyl; R₅ is isopropylthio and R₁₀ is trifluoromethyl; R₅ is cyclopentoxy and R₁₀ is trifluoromethyl; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is trifluoromethyl; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl, R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 4-isopropylbenzyloxy and R₁₀ is trifluoromethyl; R₅ is 1-phenylethoxy and R₁₀ is trifluoromethyl; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is trifluoromethyl; R₅ is 3-trifluoromethylphenyl and R₁₀ is trifluoromethyl; R₅ is 4-methoxyphenylamino and R₁₀ is trifluoromethyl; R₅ is 4-nitrophenylthio and R₁₀ is trifluoromethyl; R₅ is 3-isopropylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2,3-dichlorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-methylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-ethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-dimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-dimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,4-dichlorophenoxy and R₁₀ is trifluoromethoxy; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is trifluoromethoxy; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-dimethylaminophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-cyclopropylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-(2-furyl)phenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-aminophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 4-propoxyphenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylphenoxy and R₁₀ is trifluoromethoxy; R₅ is 2-nitrophenoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-difluorobenzyloxy and R₁₀ is trifluoromethoxy; R₅ is cyclohexylmethyleneoxy and R₁₀ is trifluoromethoxy; R₅ is benzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-ethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is isopropoxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylbenzyl and R₁₀ is trifluoromethoxy; R₅ is isopropylthio and R₁₀ is trifluoromethoxy; R₅ is cyclopentoxy and R₁₀ is trifluoromethoxy; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 4-isopropylbenzyloxy and R₁₀ is trifluoromethoxy; R₅ is 1-phenylethoxy and R₁₀ is trifluoromethoxy; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is trifluoromethoxy; R₅ is 3-trifluoromethylphenyl and R₁₀ is trifluoromethoxy; R₅ is 4-methoxyphenylamino and R₁₀ is trifluoromethoxy; R₅ is 4-nitrophenylthio and R₁₀ is trifluoromethoxy; R₅ is 3-isopropylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2,3-dichlorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2,3-trifluorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-methylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-fluoro-5-bromophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-chloro-3-ethylphenoxy and R₁₀ is 1, 1,2,2-tetrafluoroethoxy; R₅ is 3-ethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-dimethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-t-butylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluoro-3-methylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4-dichlorophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 5,6,7,8-tetrahydro-2-naphthoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-(1,1,2,2-tetrafluoroethoxy)phenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-difluoromethoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-dimethylaminophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅is 3-cyclopropylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-(2-furyl)phenoxy and R₁₀ is 1,1,2,2-tetraifluoroethoxy; R₅ is 3-pentafluoroethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-aminophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4,5-trimethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-propoxyphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylphenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-nitrophenoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethoxybenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-difluorobenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is cyclohexylmethyleneoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is benzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,5-ditrifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-trifluoromethoxybenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-ethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is isopropoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylbenzyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is isopropylthio and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is cyclopentoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-chloro-5-pyridinyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylthiobenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3,4-dimethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 2-fluoro-3-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-fluoro-5-trifluoromethylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-isopropylbenzyloxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 1-phenylethoxy and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-fluoro-3-methylbenzoyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 3-trifluoromethylphenyl and R₁₀ is 1,1,2,2-tetrafluoroethoxy; R₅ is 4-methoxyphenylamino and R₁₀ is 1,1,2,2-tetrafluoroethoxy; and R₅ is 4-nitrophenylthio and R₁₀ is 1,1,2,2-tetrafluoroethoxy.
 28. The method of claim 19 further characterized by treating coronary artery disease in a subject by administering a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt thereof.
 29. The method of claim 19 further characterized by preventing coronary artery disease in a subject by administering a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt thereof.
 30. The method of claim 19 further characterized by preventing cerebral vascular accident (CVA) in a subject by administering a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt thereof.
 31. The method of claim 19 further characterized by treating or preventing dyslipidemia in a subject by administering a therapeutically effective amount of a compound of claim 19 or a pharmaceutically acceptable salt thereof. 